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Figure 2: Effect of venlafaxine on the pharmacokinetics interacting drugs and their active metabolites.

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Interacting Drug	Interaction
Drugs known to prolong QT interval (e.g., Class IA and Class III antiarrhythmic agents).	Quinine sulfate capsules prolong QT interval, ECG abnormalities including QT prolongation and Torsades de pointes. Avoid concomitant use. (5.3)
Other antimalarials (e.g., halofantrine, mefloquine).	ECG abnormalities including QT prolongation. Avoid concomitant use. (5.3, 7.2)
CYP3A4 inducers or inhibitors	Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine. (7.1)
CYP3A4 and CYP2D6 substrates	Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the coadministered drug. (7.2)
Digoxin	Increased digoxin plasma concentration. (5.8, 7.1)

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Drugs that Affect Renal Function	A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics	Dofetilide	Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
	Sotalol	Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
	Dronedarone	Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog	Teriparatide	Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement	Thyroid	Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics	Epinephrine Norepinephrine Dopamine	Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents	Succinylcholine	May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements	Calcium	If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers		Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.

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AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide Is not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Drugs That Interfere with Hemostasis
Clinical Impact:	• Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	• During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

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Drugs That Interfere with Hemostasis
Clinical Impact:	• Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	• During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.^*
* Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol,	felodipine	norfloxacin
systemic and inhaled	finasteride	ofloxacin
amoxicillin	hydrocortisone	omeprazole
ampicillin,	isoflurane	prednisone, prednisolone
with or without sulbactam	isoniazid	ranitidine
atenolol	isradipine	rifabutin
azithromycin	influenza vaccine	roxithromycin
caffeine,	ketoconazole	sorbitol
dietary ingestion	lomefloxacin	(purgative doses do not
cefaclor	mebendazole	inhibit theophylline
co-trimoxazole	medroxyprogesterone	absorption)
(trimethoprim	methylprednisolone	sucralfate
sulfamethoxazole)	metronidazole	terbutaline, systemic
diltiazem	metoprolol	terfenadine
dirithromycin	nadolol	tetracycline
enflurane	nifedipine	tocainide
famotidine	nizatidine

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Table 4: Clinically Relevant Interactions Affecting Omeprazole When Co-Administered with Other Drugs
CYP2C19 or CYP3A4 Inducers
Clinical Impact:	Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention:	St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions (5.9)]. Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:	Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
Intervention:	Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole.

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Table 2 Clinically Significant Drug Interactions with Indomethacin
Drugs That Interfere with Hemostasis
Clinical Impact:	Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of indomethacin extended-release capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention:	Concomitant use of indomethacin extended-release capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Indomethacin extended-release capsules are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of indomethacin extended-release capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of indomethacin extended-release capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. It has been reported that the addition of triamterene to a maintenance schedule of indomethacin extended-release capsules resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin extended-release capsules and triamterene should not be administered together. Both indomethacin extended-release capsules and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin extended-release capsules and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently.
Intervention:	Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin extended-release capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact:	The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of indomethacin extended-release capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of indomethacin extended-release capsules and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of indomethacin extended-release capsules and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of indomethacin extended-release capsules and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of indomethacin extended-release capsules and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin [see Clinical Pharmacology (12.3)]. In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage.
Intervention:	The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of indomethacin extended-release capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of indomethacin extended-release capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Probenecid
Clinical Impact:	When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased.
Intervention:	During the concomitant use of indomethacin extended-release capsules and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments.

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Antiretrovirals
Clinical Impact:	The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3)]. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)]. There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
Intervention:	Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications (4)]. Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:	Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention:	Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact:	Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].
Intervention:	A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact:	Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)]. There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention:	Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6)].
Citalopram
Clinical Impact:	Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention:	Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:	Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].
Intervention:	Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:	Potential for increased exposure of phenytoin.
Intervention:	Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:	Increased exposure of diazepam [see Clinical Pharmacology (12.3)].
Intervention:	Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:	Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention:	Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:	Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:	Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)]. See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:	Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated.
	Amoxicillin also has drug interactions.
Intervention:	See Contraindications, Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact:	Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention:	Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:	Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10), Clinical Pharmacology (12.2)].
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:	Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact:	There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:	An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:	There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:	Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.

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Antiretrovirals
Clinical Impact:	The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology ( 12.3)] . Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology ( 12.3)] . There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
Intervention:	Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications ( 4)] . Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:	Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention:	Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact:	Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions ( 5.11)] .
Intervention:	A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact:	Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology ( 12.3)] . There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention:	Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions ( 5.6)] .
Citalopram
Clinical Impact:	Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology ( 12.3)] .
Intervention:	Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:	Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology ( 12.3)] .
Intervention:	Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:	Potential for increased exposure of phenytoin.
Intervention:	Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:	Increased exposure of diazepam [see Clinical Pharmacology ( 12.3)] .
Intervention:	Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:	Potential for increased exposure of digoxin [see Clinical Pharmacology ( 12.3)] .
Intervention:	Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:	Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:	Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology ( 12.3)] . See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:	Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated.
	Amoxicillin also has drug interactions.
Intervention:	See Contraindications, Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact:	Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention:	Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:	Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions ( 5.10), Clinical Pharmacology ( 12.2)] .
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:	Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology ( 12.2)] .
False Positive Urine Tests for THC
Clinical Impact:	There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:	An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:	There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:	Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.

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Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)].
Examples:	Benzodiazepines and other sedative hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue morphine sulfate extended-release tablets if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.6)].
Intervention:	Do not use morphine sulfate extended-release tablets in patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of morphine sulfate extended-release tablets and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of morphine sulfate extended-release tablets and/or the muscle relaxant as necessary.
Cimetidine
Clinical Impact:	The concomitant use of cimetidine can potentiate morphine effects and increase risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of morphine sulfate extended-release tablets and/or cimetidine as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when morphine sulfate extended-release tablets are used concomitantly with anticholinergic drugs.
P-Glycoprotein (P-gp) Inhibitors
Clinical Impact:	The concomitant use of PGP-inhibitors can increase the exposure to morphine by about two-fold and can increase risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of morphine sulfate extended-release tablets and/or the PGP-inhibitor as necessary.
Example:	quinidine

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AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide Is not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Drugs That Interfere with Hemostasis
Clinical Impact:	• Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	• During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

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Drugs that Affect Renal Function	A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics	Dofetilide	Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
	Sotalol	Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
	Dronedarone	Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog	Teriparatide	Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement	Thyroid	Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics	Epinephrine Norepinephrine Dopamine	Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents	Succinylcholine	May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements	Calcium	If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers		Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.

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Table 4. Mean (95% C.I.) maximal change in baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in healthy volunteers on daily alpha-blocker therapy
		Dosing of Vardenafil and Alpha-Blocker Separated by 6 Hours		Simultaneous dosing of Vardenafil and Alpha-Blocker
Alpha-Blocker		Vardenafil 10 mg Placebo-Subtracted	Vardenafil 20 mg Placebo-Subtracted	Vardenafil 10 mg Placebo-Subtracted	Vardenafil 20 mg Placebo-Subtracted
Terazosin 10 mg daily	Standing SBP	-7 (-10, -3)	-11 (-14, -7)	-23 (-31, 16) Due to the sample size, confidence intervals may not be an accurate measure for these data. These values represent the range for the difference.	-14 (-33, 11)
Terazosin 10 mg daily	Supine SBP	-5 (-8, -2)	-7 (-11, -4)	-7 (-25, 19)	-7 (-31, 22)
Tamsulosin 0.4 mg daily	Standing SBP	-4 (-8, -1)	-8 (-11, -4)	-8 (-14, -2)	-8 (-14, -1)
	Supine SBP	-4 (-8, 0)	-7 (-11, -3)	-5 (-9, -2)	-3 (-7, 0)

Table name:

Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Drugs that May Increase the Risk of Hypoglycemia
Drugs:	Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analog (e.g., octreotide), and sulfonamide antibiotics
Intervention:	Dose adjustment and increased frequency of glucose monitoring may be required when NOVOLOG MIX 70/30 is co-administered with these drugs.
Drugs that May Decrease the Blood Glucose Lowering Effect of NOVOLOG MIX 70/30
Drugs:	Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones.
Intervention:	Dose adjustment and increased frequency of glucose monitoring may be required when NOVOLOG MIX 70/30 is co-administered with these drugs.
Drugs that May Increase or Decrease the Blood Glucose Lowering Effect ofNOVOLOG MIX 70/30
Drugs:	Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.
Intervention:	Dose adjustment and increased frequency of glucose monitoring may be required when NOVOLOG MIX 70/30 is co-administered with these drugs.
Drugs that May Blunt Signs and Symptoms of Hypoglycemia
Drugs:	Beta-blockers, clonidine, guanethidine, and reserpine
Intervention:	Increased frequency of glucose monitoring may be required when NOVOLOG MIX 70/30 is co-administered with these drugs.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T ₄ and T ₃levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT ₄ . Continued administration results in a decrease in serum T ₄ and normal FT ₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T ₄ and T ₃ to TBG and transthyretin. An initial increase in serum FT ₄ is followed by return of FT ₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T ₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T ₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T ₄ to T ₃, leading to decreased T ₃ levels. However, serum T ₄levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T ₃ and T ₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T ₃concentrations by 30% with minimal change in serum T ₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T ₃ and T ₄levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³ I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine concentrations approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine and carbamazepine epoxide	? carbamazepine epoxide	May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Drugs That Interfere with Hemostasis
Clinical Impact:	Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of indomethacin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions ( 5.11 )].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions ( 5.2 ) ].
Intervention:	Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions ( 5.11 )].Indomethacin is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of indomethacin capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.During concomitant use of indomethacin capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions ( 5.6 )].When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.It has been reported that the addition of triamterene to a maintenance schedule of Indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together.Both indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently [ see Warnings and Precautions ( 5.6 )].
Intervention:	Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels. [ see Warnings and Precautions ( 5.6 )].
Digoxin
Clinical Impact:	The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention:	During concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions ( 5.2 )]. Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin [see Clinical Pharmacology ( 12.3 )].In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage.
Intervention:	The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Probenecid
Clinical Impact:	When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased.
Intervention:	During the concomitant use of indomethacin and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments.

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Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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^a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. ^b = Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. NE = Not Evaluated.
AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Drug	Description of Interaction
Tolbutamide; Sulfonylureas	Hypoglycemia potentiated
Methotrexate	Decreases tubular reabsorption; clinical toxicity from methotrexate can result
Oral Anticoagulant	Increased bleeding

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Interacting Drug	Interaction
Antacids, sucralfate, multivitamins, and other products containing multivalent cations	Moxifloxacin absorption is decreased. Administer moxifloxacin hydrochloride tablet at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3, 17.2)
Warfarin	Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. (6.4, 7.2, 12.3)
Class IA and Class III antiarrhythmics:	Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.3, 7.4)

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Specific Drugs Reported
also: other medications affecting blood elements which may modify hemostasis dietary deficiencies prolonged hot weather unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported.
acetaminophen alcohol† allopurinol aminosalicylic acid amiodarone HCl argatroban aspirin atenolol atorvastatin† azithromycin bivalirudin capecitabine cefamandole cefazolin cefoperazone cefotetan cefoxitin ceftriaxone celecoxib cerivastatin chenodiol chloramphenicol chloral hydrate† chlorpropamide cholestyramine† cimetidine ciprofloxacin cisapride clarithromycin clofibrate cyclophosphamide† danazol dextran dextrothyroxine diazoxide	diclofenac dicumarol diflunisal disulfiram doxycycline erythromycin esomeprazole ethacrynic acid ezetimibe fenofibrate fenoprofen fluconazole fluorouracil fluoxetine flutamide fluvastatin fluvoxamine gefitinib gemifibrozil glucagon halothane heparin ibuprofen ifosfamide indomethacin influenza virus vaccine itraconazole ketoprofen ketorolac lansoprazole lepirudin levamisole levofloxacin levothyroxine liothyronine	lovastatin mefenamic acid methimazole† methyldopa methylphenidate methylsalicylate ointment (topical) metronidazole miconazole (intravaginal, oral, systemic) moricizine hydrochloride† nalidixic acid naproxen neomycin norfloxacin ofloxacin olsalazine omeprazole oxandrolone oxaprozin oxymetholone pantoprazole paroxetine penicillin G, intravenous pentoxifylline phenylbutazone phenytoin† piperacillin piroxicam pravastatin† prednisone† propafenone	propoxyphene propranolol propylthiouracil† quinidine quinine rabeprazole ranitidine† rofecoxib sertraline simvastatin stanozolol streptokinase sulfamethizole sulfamethoxazole sulfinpyrazone sulfisoxazole sulindac tamoxifen tetracycline thyroid ticarcillin ticlopidine tissue plasminogen activator (t-PA) tolbutamide tramadol trimethoprim/ sulfamethoxazole urokinase valdecoxib valproate vitamin E warfarin overdose zafirlukast zileuton

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Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
*Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	C_m _a _x
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing.

	20 mg/day	4 mg/day	1.6	-	Do not exceed 8 mg/day
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Drugs That Interfere with Hemostasis
Clinical Impact:	• Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	• During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

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TABLE 2. Mean (± S.D.) Pharmacokinetic Parameters for Estradiol, Estrone, and Equilin Following Coadministration of Conjugated Estrogens 0.625 mg and PROMETRIUM Capsules 200 mg for 12 Days to Postmenopausal Women
^a Total estrogens is the sum of conjugated and unconjugated estrogen.
	Conjugated Estrogens			Conjugated Estrogens plus PROMETRIUM Capsules
Drug	Cmax (ng/mL)	Tmax (hr)	AUC(0-24h) (ng × h/mL)	Cmax (ng/mL)	Tmax (hr)	AUC(0-24h) (ng × h/mL)
Estradiol	0.037 ± 0.048	12.7 ± 9.1	0.676 ± 0.737	0.030 ± 0.032	17.32 ± 1.21	0.561 ± 0.572
Estrone Total^a	3.68 ± 1.55	10.6 ± 6.8	61.3 ± 26.36	4.93 ± 2.07	7.5 ± 3.8	85.9 ± 41.2
Equilin Total^a	2.27 ± 0.95	6.0 ± 4.0	28.8 ± 13.0	3.22 ± 1.13	5.3 ± 2.6	38.1 ± 20.2

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Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
Drug Name	Effect on Concentration of Nevirapine or Concomitant Drug	Clinical Comment
Atazanavir/Ritonavir	↓ Atazanavir ↑ Nevirapine	Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure.
Clarithromycin	↓ Clarithromycin ↑ 14-OH clarithromycin	Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex , overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Efavirenz	↓ Efavirenz	There has been no determination of appropriate doses for the safe and effective use of this combination [ see Warnings and Precautions (5.4) ].
Ethinyl estradiol and Norethindrone	↓ Ethinyl estradiol ↓ Norethindrone	Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.
Fluconazole	↑Nevirapine	Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Fosamprenavir	↓ Amprenavir ↑ Nevirapine	Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir	↓ Amprenavir ↑ Nevirapine	No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily.
Indinavir	↓ Indinavir	Appropriate doses for this combination are not established, but an increase in the dosage of indinavir may be required.
Ketoconazole	↓ Ketoconazole	Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Lopinavir/Ritonavir	↓Lopinavir	Lopinavir/ritonavir 400/100 mg tablets can be used twice daily in combination with nevirapine with no dose adjustment in antiretroviral-naïve patients. A dose increase of lopinavir/ritonavir tablets to 600/150 mg (3 tablets) twice daily may be considered when used in combination with nevirapine in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). A dose increase of lopinavir/ritonavir oral solution to 533/133 mg twice daily with food is recommended in combination with nevirapine. In children 6 months to 12 years of age, consideration should be given to increasing the dose of lopinavir/ritonavir to 13/3.25 mg/kg for those 7 to <15 kg; 11/2.75 mg/kg for those 15 to 45 kg; and up to a maximum dose of 533/133 mg for those >45 kg twice daily when used in combination with nevirapine, particularly for patients in whom reduced susceptibility to lopinavir/ritonavir is suspected.
Methadone	↓ Methadone	Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Nelfinavir	↓Nelfinavir M8 Metabolite ↓Nelfinavir C_min	The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established.
Rifabutin	↑Rifabutin	Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin	↓ Nevirapine	Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Saquinavir/ritonavir	The interaction between VIRAMUNE and saquinavir/ritonavir has not been evaluated	The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
Potential Drug Interactions:
Drug Class	Examples of Drugs
Antiarrhythmics	Amiodarone, disopyramide, lidocaine	Plasma concentrations may be decreased.
Anticonvulsants	Carbamazepine, clonazepam, ethosuximide	Plasma concentrations may be decreased.
Antifungals	Itraconazole	Plasma concentrations of some azole antifungals may be decreased. Nevirapine and itraconazole should not be administered concomitantly due to a potential decrease in itraconazole plasma concentrations.
Calcium channel blockers	Diltiazem, nifedipine, verapamil	Plasma concentrations may be decreased.
Cancer chemotherapy	Cyclophosphamide	Plasma concentrations may be decreased.
Ergot alkaloids	Ergotamine	Plasma concentrations may be decreased.
Immunosuppressants	Cyclosporin, tacrolimus, sirolimus	Plasma concentrations may be decreased.
Motility agents	Cisapride	Plasma concentrations may be decreased.
Opiate agonists	Fentanyl	Plasma concentrations may be decreased.
Antithrombotics	Warfarin	Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.

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Table 3Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Table 2: Drug-Thyroidal Axis Interactions
	Drug or Drug Class		Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
		Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
		Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
		Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
		Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
		Amiodarone Iodide (including iodine- containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
	Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
	Drugs that may increase		Drugs that may decrease
	serum TBG concentration		serum TBG concentration
	Clofibrate		Androgens / Anabolic Steroids
	Estrogen-containing oral		Asparaginase
	contraceptives		Glucocorticoids
	Estrogens (oral)		Slow-Release Nicotinic Acid
	Heroin / Methadone
	5-Fluorouracil
	Mitotane
	Tamoxifen
	Drugs that may cause protein-binding site displacement
	Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)		Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
	Carbamazepine Hydantoins Phenobarbital Rifampin		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
	Drugs that may decrease T ₄ 5' - deiodinase activity
	Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)		Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, Ieading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
	Miscellaneous
	Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives		Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
	Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
	Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin		Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
	Cardiac Glycosides		Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
	Cytokines - Interferon-α - Interleukin-2		Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
	Growth Hormones - Somatrem - Somatropin		Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
	Ketamine		Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
	Methylxanthine Bronchodilators - (e.g., Theophylline)		Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
	Radiographic Agents		Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
	Sympathomimetics		Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
	Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics		These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 3: Clinically Important Drug Interactions with Repaglinide Tablets
Gemfibrozil
Clinical Impact:	Gemfibrozil significantly increased repaglinide exposures by 8.1 fold [see Clinical Pharmacology (12.3)]
Intervention:	Do not administer repaglinide tablets to patients receiving gemfibrozil [see Contraindications (4)].
Clopidogrel
Clinical Impact:	Clopidogrel increased repaglinide exposures by 3.9-5.1 fold [see Clinical Pharmacology (12.3)]
Intervention:	Avoid concomitant use of repaglinide tablets with clopidogrel. If concomitant use cannot be avoided, initiate repaglinide tablets at 0.5 mg before each meal and do not exceed a total daily dose of 4 mg [see DOSAGE AND ADMINISTRATION (2.3)]. Increased frequency of glucose monitoring may be required during concomitant use.
Cyclosporine
Clinical Impact:	Cyclosporine increased low dose repaglinide exposures by 2.5 fold [see Clinical Pharmacology (12.3)]
Intervention:	Daily maximum repaglinide tablets dose should be limited to 6 mg, and increased frequency of glucose monitoring may be required when repaglinide tablets is co-administered with cyclosporine.
CYP2C8 and CYP3A4 Inhibitors
Intervention:	Repaglinide tablets dose reductions and increased frequency of glucose monitoring may be required when co-administered.
Examples:	Drugs that are known to inhibit CYP3A4 include antifungal agents (ketoconazole, itraconazole) and antibacterial agents (clarithromycin, erythromycin). Drugs that are known to inhibit CYP2C8 include trimethoprim, gemfibrozil, montelukast, deferasirox, and clopidiogrel.
CYP2C8 and CYP3A4 Inducers
Intervention:	Repaglinide tablets dose increases and increased frequency of glucose monitoring may be required when co-administered.
Examples:	Drugs that induce the CYP3A4 and/or 2C8 enzyme systems include rifampin, barbiturates, and carbamezapine
Drugs That May Increase the Risk of Hypoglycemia
Intervention:	Repaglinide tablets dose reductions and increased frequency of glucose monitoring may be required when co-administered.
Examples:	Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, nonsteroidal anti-inflammatory agents (NSAIDs), pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics
Drugs That May Decrease the Blood Glucose Lowering Effect of Repaglinide Tablets
Intervention:	Repaglinide tablets dose increases and increased frequency of glucose monitoring may be required when co-administered.
Examples:	Atypical antipsychotics (e.g., olanzapine and clozapine), calcium channel antagonists, corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones.
Drugs That May Blunt Signs and Symptoms of Hypoglycemia
Intervention:	Increased frequency of glucose monitoring may be required when repaglinide tablets are co-administered with these drugs.
Examples:	beta-blockers, clonidine, guanethidine, and reserpine

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Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Interacting Drug	Interaction
Antacids, sucralfate, multivitamins, and other products containing multivalent cations	Moxifloxacin absorption is decreased. Administer AVELOX Tablet at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3, 17.2)
Warfarin	Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. (6.4, 7.2, 12.3)
Class IA and Class III antiarrhythmics:	Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.3, 7.4)

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Factors	Dosage Adjustments for REXULTI (2.5)
Strong CYP2D6* or CYP3A4 inhibitors	Administer half of usual dose
Strong/moderate CYP2D6 with Strong/moderate CYP3A4 inhibitors	Administer a quarter of usual dose
Known CYP2D6 Poor Metabolizers taking strong/moderate CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double the usual dose and further adjust based on clinical response

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AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide Is not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)]
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.9)].
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.11) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs [see Adverse Reactions (6.1)].
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions (5.16)].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution Two-fold increase in exposure	Monitor for sildenafil toxicity [see Clinical Pharmacology (12.3)].
Duloxetine	Avoid Use Five-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2.4)].	Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
* Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing.
	20 mg/day	4 mg/day	1.6	-	Do not exceed 8 mg/day
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed

Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 7.8, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 Inhibitors, (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with VYTORIN
Verapamil, diltiazem, dronedarone	Do not exceed 10/10 mg VYTORIN daily
Amiodarone, amlodipine, ranolazine	Do not exceed 10/20 mg VYTORIN daily
Lomitapide	For patients with HoFH, do not exceed 10/20 mg VYTORIN daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 10/40 mg VYTORIN when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Table II. Clinically significant drug interactions with theophylline Refer to PRECAUTIONS, Drug Interactions for further information regarding table. .
Drug	Type of Interaction	Effect Average effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine	Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.
Alcohol	A single large dose of alcohol (3 ml/kg of whiskey) decreases theophylline clearance for up to 24 hours.	30% increase
Allopurinol	Decreases theophylline clearance doses ≥600 mg/day.	25% increase at allopurinol
Amino glutethimide	Increases theophylline clearance by induction of microsomal enzyme activity.	25% decrease
Carbamazepine	Similar to aminoglutethimide.	30% decrease
Cimetidine	Decreases theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase
Ciprofloxacin	Similar to cimetidine.	40% increase
Clarithromycin	Similar to erythromycin.	25% increase
Diazepam	Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.	Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram	Decreases theophylline clearance by inhibiting hydroxylation and demethylation.	50% increase
Enoxacin	Similar to cimetidine.	300% increase
Ephedrine	Synergistic CNS effects.	Increased frequency of nausea, nervousness, and insomnia.
Erythromycin	Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen	Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.	30% increase
Flurazepam	Similar to diazepam.	Similar to diazepam.
Fluvoxamine	Similar to cimetidine.	Similar to cimetidine.
Halothane	Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.	Increased risk of ventricular arrhythmias
Interferon, human recombinant alpha-A	Decreases theophylline clearance.	100% increase
Isoproterenol (IV)	Increases theophylline clearance.	20% decrease
Ketamine	Pharmacologic	May lower theophylline seizure threshold.
Lithium	Theophylline increases renal lithium clearance.	Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam	Similar to diazepam.	Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.	20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine	Similar to disulfiram.	80% increase
Midazolam	Similar to diazepam.	Similar to diazepam.
Moricizine	Increases theophylline clearance.	25% decrease
Pancuronium	Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.	Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline	Decreases theophylline clearance.	30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.	25% decrease after two weeks of concurrent PB.
Phenytoin	Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.	Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone	Decreases theophylline clearance and pharmacologic interaction.	40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and pharmacologic interaction.	100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin	Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.	20-40% decrease
Sulfinpyrazone	Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.	20% decrease
Tacrine	Similar to cimetidine, also increases renal clearance of theophylline.	90% increase
Thiabendazole	Decreases theophylline clearance.	190% increase
Ticlopidine	Decreases theophylline clearance.	60% increase
Troleandomycin	Similar to erythromycin.	33-100% increase depending on troleandomycin dose.
Verapamil	Similar to disulfiram.	20% increase

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
↓= Decreased (induces lamotrigine gluronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ?= Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
	? CBZ epoxide	May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table II. Clinically significant drug interactions with theophylline.Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
Drug	Type of Interaction	Effect Average effect on steady-state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine	Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.
Alcohol	A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours.	30% increase
Allopurinol	Decreases theophylline clearance at allopurinol doses ≥600 mg/day.	25% increase
Aminoglutethimide	Increases theophylline clearance by induction of microsomal enzyme activity.	25% decrease
Carbamazepine	Similar to aminoglutethimide.	30% decrease
Cimetidine	Decreases theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase
Ciprofloxacin	Similar to cimetidine.	40% increase
Clarithromycin	Similar to erythromycin.	25% increase
Diazepam	Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.	Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram	Decreases theophylline clearance by inhibiting hydroxylation and demethylation.	50% increase
Enoxacin	Similar to cimetidine.	300% increase
Ephedrine	Synergistic CNS effects	Increased frequency of nausea, nervousness, and insomnia.
Erythromycin	Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen	Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.	30% increase
Flurazepam	Similar to diazepam.	Similar to diazepam.
Fluvoxamine	Similar to cimetidine.	Similar to cimetidine.
Halothane	Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.	Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A	Decreases theophylline clearance.	100% increase
Isoproterenol (IV)	Increase theophylline clearance.	20% increase
Ketamine	Pharmacologic	May lower theophylline seizure threshold.
Lithium	Theophylline increases renal lithium clearance.	Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam	Similar to diazepam.	Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.	20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine	Similar to disulfiram.	80% increase
Midazolam	Similar to diazepam.	Similar to diazepam.
Moricizine	Increases theophylline clearance.	25% decrease
Pancuronium	Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.	Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline	Decreases theophylline clearance.	30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.	25% decrease after two weeks of concurrent PB.
Phenytoin	Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.	Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone	Decreases theophylline clearance and pharmacologic interaction.	40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and pharmacologic interaction.	100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin	Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.	20 to 40% decrease
Sulfinpyrazone	Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.	20% increase
Tacrine	Similar to cimetidine, also increases renal clearance of theophylline.	90% increase
Thiabendazole	Decreases theophylline clearance.	190% increase
Ticlopidine	Decreases theophylline clearance.	60% increase
Troleandomycin	Similar to erythromycin.	33 to 100% increase depending on troleandomycin dose.
Verapamil	Similar to disulfiram.	20% increase

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Table 5. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on
	Concentration of
	Lamotrigine or
	Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.

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Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.7)].
Benzodiazepines (e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.7)]	Monitor sedation and blood pressure. Adjust dose accordingly.

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Table 3. Drugs That May Alter T4 and Triiodothyronine (T3) Serum Transport Without Affecting Free Thyroxine (FT4) Concentration (Euthyroidism)
Drug or Drug Class	Effect
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	These drugs may increase serum thyroxine-binding globulin (TBG) concentration.
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid	These drugs may decrease serum TBG concentration.
Potential impact (below): Administration of these agents with SYNTHROID results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations.
Salicylates (> 2 g/day)	Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total T4 levels may decrease by as much as 30%.
Other drugs: Carbamazepine Furosemide (> 80 mg IV) Heparin Hydantoins Non-Steroidal Anti-inflammatory Drugs - Fenamates	These drugs may cause protein-binding site displacement. Furosemide has been shown to inhibit the protein binding of T4 to TBG and albumin, causing an increase free T4 fraction in serum. Furosemide competes for T4-binding sites on TBG, prealbumin, and albumin, so that a single high dose can acutely lower the total T4 level. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total and free T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. Closely monitor thyroid hormone parameters.

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Benzodiazepines
Clinical Impact:	There have been a number of reports regarding coma and death associated with the misuse and abuse of the combination of buprenorphine and benzodiazepines. In many, but not all of these cases, buprenorphine was misused by self-injection of crushed buprenorphine tablets. Preclinical studies have shown that the combination of benzodiazepines and buprenorphine altered the usual ceiling effect on buprenorphine-induced respiratory depression, making the respiratory effects of buprenorphine appear similar to those of full opioid agonists.
Intervention:	Closely monitor patients with concurrent use of buprenorphine and benzodiazepines. Warn patients that it is extremely dangerous to self-administer benzodiazepines while taking buprenorphine, and warn patients to use benzodiazepines concurrently with buprenorphine only as directed by their healthcare provider.
Non-Benzodiazepine Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effects, the concomitant use of non-benzodiazepine CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.2, 5.3)].
Examples:	Alcohol, non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids.
Inhibitors of CYP3A4
Clinical Impact:	The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of buprenorphine is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease [see Clinical Pharmacology (12.3)], potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to buprenorphine.
Intervention:	If concomitant use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples:	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact:	The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine [see Clinical Pharmacology (12.3)], potentially resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both therapeutic effects and adverse reactions and may cause serious respiratory depression.
Intervention:	If concomitant use is necessary, consider increasing the buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider buprenorphine dosage reduction and monitor for signs of respiratory depression.
Examples:	Rifampin, carbamazepine, phenytoin
Antiretrovirals: Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Clinical Impact:	Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine, and etravirine are known CYP3A inducers, whereas delaviridine is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects.
Intervention:	Patients who are on chronic buprenorphine treatment should have their dose monitored if NNRTIs are added to their treatment regimen.
Examples:	efavirenz, nevirapine, etravirine, delavirdine
Antiretrovirals: Protease inhibitors (PIs)
Clinical Impact:	Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity (atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine, and patients in one study reported increased sedation. Symptoms of opioid excess have been found in postmarketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly.
Intervention:	Monitor patients taking buprenorphine and atazanavir with and without ritonavir, and reduce dose of buprenorphine if warranted.
Examples:	atazanavir, ritonavir
Antiretrovirals: Nucleoside reverse transcriptase inhibitors (NRTIs)
Clinical Impact:	Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected.
Intervention:	None
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue buprenorphine if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).
Intervention:	The use of buprenorphine is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Muscle Relaxants
Clinical Impact:	Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients receiving muscle relaxants and buprenorphine for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of buprenorphine and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when buprenorphine is used concomitantly with anticholinergic drugs.

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Table 4: Clinically Relevant Interactions Affecting Omeprazole When Co-Administered with Other Drugs
CYP2C19 or CYP3A4 Inducers
Clinical Impact:	Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology ( 12.3)].
Intervention:	St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions ( 5.9)]. Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:	Increased exposure of omeprazole [see Clinical Pharmacology ( 12.3)].
Intervention:	Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole.

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Table 7: Effect of Other Drugs on Voriconazole Pharmacokinetics
[see Clinical Pharmacology (12.3) ]
Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (C_maxand AUC_τafter 200 mg every 12h)	Recommendations for Voriconazole Dosage Adjustment/Comments
Rifampin* and Rifabutin* (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (400 mg daily) (CYP450 Induction) Efavirenz (300 mg daily) (CYP450 Induction)	Significantly Reduced	Contraindicated
High-dose Ritonavir (400 mg every 12h) (CYP450 Induction) Low-dose Ritonavir (100 mg every 12h) (CYP450 Induction)	Significantly Reduced Reduced	Contraindicated Coadministration of voriconazole and low-dose ritonavir (100 mg every 12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro , but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (CYP450 Induction)	Not Studied In Vivo or In Vitro , but Likely to Result in Significant Reduction	Contraindicated
Phenytoin* (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV every 12h or from 200 mg to 400 mg orally every 12h (100 mg to 200 mg orally every 12h in patients weighing less than 40 kg)
St. John’s Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives** containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole** (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIs*** (CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure) A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to voriconazole Careful assessment of voriconazole effectiveness
Everolimus (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Concomitant administration of voriconazole and everolimus is not recommended.
* Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg every 12h voriconazole to healthy subjects Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12h for 1 day, then 200 mg every 12h for at least 2 days voriconazole to healthy subjects * Non-Nucleoside Reverse Transcriptase Inhibitors

Table name:

Drugs That Interfere with Hemostasis
Clinical Impact:	• Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	• During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

Table name:

Inhibitors of CYP3A4 and CYP2D6
Clinical Impact:	The concomitant use of oxycodone hydrochloride tablets and CYP3A4 inhibitors can increase the plasma concentration of oxycodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of oxycodone hydrochloride tablets and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of oxycodone is achieved [see Warnings and Precautions (5.4)]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the oxycodone plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to oxycodone.
Intervention:	If concomitant use is necessary, consider dosage reduction of oxycodone hydrochloride tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the oxycodone hydrochloride tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples:	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir).
CYP3A4 Inducers
Clinical Impact:	The concomitant use of oxycodone hydrochloride tablets and CYP3A4 inducers can decrease the plasma concentration of oxycodone [see Clinical Pharmacology (12.3)] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to oxycodone [see Warnings and Precautions (5.12)]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the oxycodone plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention:	If concomitant use is necessary, consider increasing the oxycodone hydrochloride tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider oxycodone hydrochloride tablets dosage reduction and monitor for signs of respiratory depression.
Examples:	Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.5)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Adverse Reactions (6.2)].
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue oxycodone hydrochloride tablets if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
Intervention:	The use of oxycodone hydrochloride tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of oxycodone hydrochloride tablets and/or may precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use
Examples:	Butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Oxycodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of oxycodone hydrochloride tablets and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of dismissed diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant risk of anticholinergic drugs may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when oxycodone hydrochloride tablets are used concurrently with anticholinergic drugs.

Table name: When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h

Table 7: Effect of Voriconazole on Pharmacokinetics of Other Drugs [see CLINICAL PHARMACOLOGY (12.3)]
Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30 to 100 mg q24h) Non-Steroidal Anti-Inflammatory Drug ***Non-Nucleoside Reverse Transcriptase Inhibitors
Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C_max and AUCτ)	Recommendations for Drug Dosage Adjustment/Comments
Sirolimus* (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin* (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (400 mg q 24h)** (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (300 mg q 24h) ** (CYP3A4 Inhibition)	Slight decrease in AUC_t
High-dose Ritonavir (400 mg q12h)** (CYP3A4 Inhibition)	No Significant Effect of Voriconazole on	Contraindicated because of significant reduction of voriconazole C_max and AUCτ
	Ritonavir C_max or AUCτ

Low-dose Ritonavir (100 mg q12h)**	Slight Decrease in Ritonavir C_max and AUCτ	Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole C_max and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated
Cyclosporine* (CYP3A4 Inhibition)	AUCτ Significantly Increased; No Significant Effect on C_max	When initiating therapy with voriconazole in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
Methadone*** (CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed.
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other longacting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see DRUG INTERACTIONS (7)].
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see DRUG INTERACTIONS (7)].
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see DRUG INTERACTIONS (7)].
NSAIDs**** including ibuprofen and diclofenac (CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed. [see DRUG INTERACTIONS (7)].
Tacrolimus* (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with voriconazole in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin* (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)**	Increased	Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin* (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	Monitor PT or other suitable anticoagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole* (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with voriconazole in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects on Indinavir Exposure	No dosage adjustment for indinavir when coadministered with voriconazole
	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIs***** (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.
Everolimus (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Concomitant administration of voriconazole and everolimus is not recommended.

Table name:

Table II. Clinically significant drug interactions with theophylline.Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
Drug	Type of Interaction	EffectAverage effect on steady-state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine	Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.
Alcohol	A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours.	30% increase
Allopurinol	Decreases theophylline clearance at allopurinol doses ≥600 mg/day.	25% increase
Aminoglutethimide	Increases theophylline clearance by induction of microsomal enzyme activity.	25% decrease
Carbamazepine	Similar to aminoglutethimide.	30% decrease
Cimetidine	Decreases theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase
Ciprofloxacin	Similar to cimetidine.	40% increase
Clarithromycin	Similar to erythromycin.	25% increase
Diazepam	Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.	Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram	Decreases theophylline clearance by inhibiting hydroxylation and demethylation.	50% increase
Enoxacin	Similar to cimetidine.	300% increase
Ephedrine	Synergistic CNS effects	Increased frequency of nausea, nervousness, and insomnia.
Erythromycin	Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen	Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.	30% increase
Flurazepam	Similar to diazepam.	Similar to diazepam.
Fluvoxamine	Similar to cimetidine.	Similar to cimetidine.
Halothane	Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.	Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A	Decreases theophylline clearance.	100% increase
Isoproterenol (IV)	Increase theophylline clearance.	20% increase
Ketamine	Pharmacologic	May lower theophylline seizure threshold.
Lithium	Theophylline increases renal lithium clearance.	Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam	Similar to diazepam.	Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.	20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine	Similar to disulfiram.	80% increase
Midazolam	Similar to diazepam.	Similar to diazepam.
Moricizine	Increases theophylline clearance.	25% decrease
Pancuronium	Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.	Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline	Decreases theophylline clearance.	30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.	25% decrease after two weeks of concurrent PB.
Phenytoin	Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.	Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone	Decreases theophylline clearance and pharmacologic interaction.	40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and pharmacologic interaction.	100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin	Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.	20 to 40% decrease
Sulfinpyrazone	Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.	20% increase
Tacrine	Similar to cimetidine, also increases renal clearance of theophylline.	90% increase
Thiabendazole	Decreases theophylline clearance.	190% increase
Ticlopidine	Decreases theophylline clearance.	60% increase
Troleandomycin	Similar to erythromycin.	33 to 100% increase depending on troleandomycin dose.
Verapamil	Similar to disulfiram.	20% increase

Table name:

Drug	Effect
Phenylephrine with prior administration of monoamine oxidase inhibitors (MAOI).	Cardiac pressor response potentiated. May cause acute hypertensive crisis.
Phenylephrine with tricyclic antidepressants.	Pressor response increased.
Phenylephrine with ergot alkaloids.	Excessive rise in blood pressure.
Phenylephrine with bronchodilator sympathomimetic agents and with epinephrine or other sympathomimetics.	Tachycardia or other arrhythmias may occur.
Phenylephrine with prior administration of propranolol or other β-adrenergic blockers.	Cardiostimulating effects blocked.
Phenylephrine with atropine sulfate.	Reflex bradycardia blocked; pressor response enhanced.
Phenylephrine with prior administration of phentolamine or other α-adrenergic blockers.	Pressor response decreased.
Phenylephrine with diet preparations, such as amphetamines or phenylpropanolamine.	Synergistic adrenergic response.

Table name:

Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine concentrations approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine and carbamazepine epoxide	? carbamazepine epoxide	May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

Table name:

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

Table name:

Table 9. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug Name	Effect on Concentration of Lopinavir or Concomitant Drug	Clinical Comments
HIV-1 Antiviral Agents
Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz, nevirapine	↓ lopinavir	KALETRA dose increase is recommended in all patients [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)]. Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz. Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz. KALETRA should not be administered once daily in combination with efavirenz or nevirapine [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine	↑ lopinavir	Appropriate doses of the combination with respect to safety and efficacy have not been established.
Nucleoside Reverse Transcriptase Inhibitor: didanosine		KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).
Nucleoside Reverse Transcriptase Inhibitor: tenofovir	↑ tenofovir	KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitor: abacavir zidovudine	↓ abacavir ↓ zidovudine	KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.
HIV-1 Protease Inhibitor: amprenavir*	↑ amprenavir ↓ lopinavir	KALETRA should not be administered once daily in combination with amprenavir [see Dosage and Administration (2.1)].
HIV-1 Protease Inhibitor: fosamprenavir/ritonavir	↓ amprenavir ↓ lopinavir	An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: indinavir*	↑ indinavir	Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily [see Clinical Pharmacology (12.3)]. KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor: nelfinavir*	↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir	KALETRA should not be administered once daily in combination with nelfinavir [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
HIV-1 Protease Inhibitor: ritonavir*	↑ lopinavir	Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: saquinavir*	↑ saquinavir	The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor: tipranavir	↓ lopinavir AUC and C_min	KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily).
HIV CCR5 – Antagonist: maraviroc	↑ maraviroc	Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry^® (maraviroc).
Other Agents
Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), quinidine	↑ antiarrhythmics	Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.
Anticancer Agents: vincristine, vinblastine, dasatinib, nilotinib	↑ anticancer agents	Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents. For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.
Anticoagulant: warfarin		Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: carbamazepine, phenobarbital, phenytoin	↓ lopinavir ↓ phenytoin	KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
Antidepressant: bupropion	↓ bupropion ↓ active metabolite, hydroxybupropion	Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant: trazodone	↑ trazodone	Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-infective: clarithromycin	↑ clarithromycin	For patients with renal impairment, the following dosage adjustments should be considered: • For patients with CL_CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. • For patients with CL_CR < 30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary.
Antifungals: ketoconazole*, itraconazole, voriconazole	↑ ketoconazole ↑ itraconazole ↓ voriconazole	High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended. Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients.
Anti-gout: colchicine	↑ colchicine	Patients with renal or hepatic impairment should not be given colchicine with KALETRA. Treatment of gout flares-co-administration of colchicine in patients on KALETRA: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on KALETRA: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial: rifabutin*	↑ rifabutin and rifabutin metabolite	Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antimycobacterial: rifampin	↓ lopinavir	May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone [see Clinical Pharmacology (12.3) for magnitude of interaction].
Antiparasitic: atovaquone	↓ atovaquone	Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Benzodiazepines: parenterally administered midazolam	↑ midazolam	Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam [see Contraindications (4)]. If KALETRA is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Calcium Channel Blockers: dihydropyridine, felodipine, nifedipine, nicardipine	↑ dihydropyridine calcium channel blockers	Caution is warranted and clinical monitoring of patients is recommended.
Contraceptive: ethinyl estradiol*	↓ ethinyl estradiol	Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.
Corticosteroid: dexamethasone	↓ lopinavir	Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly.
disulfiram/metronidazole		KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Endothelin Receptor Antagonists: bosentan	↑ bosentan	Co-administration of bosentan in patients on KALETRA: In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Co-administration of KALETRA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA. After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin	↑ atorvastatin ↑ rosuvastatin	Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day. See Drugs with No Observed or Predicted Interactions with KALETRA (7.4) and Clinical Pharmacology (12.3) for drug interaction data with other HMG-CoA reductase inhibitors.
Immunosuppressants: cyclosporine, tacrolimus, rapamycin	↑ immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Inhaled Steroid: fluticasone	↑ fluticasone	Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect.
Long-acting beta-adrenoceptor Agonist: salmeterol	↑ salmeterol	Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic: methadone* fentanyl	↓ methadone ↑ fentanyl	Dosage of methadone may need to be increased when co-administered with KALETRA. Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA.
PDE5 inhibitors: sildenafil, tadalafil, vardenafil	↑ sildenafil ↑ tadalafil ↑ vardenafil	Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio^®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA [see Contraindications (4)]. The following dose adjustments are recommended for use of tadalafil (Adcirca^®) with KALETRA: Co-administration of ADCIRCA in patients on KALETRA: In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Co-administration of KALETRA in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: It is recommended not to exceed the following doses: • Sildenafil: 25 mg every 48 hours • Tadalafil: 10 mg every 72 hours • Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events.
* see Clinical Pharmacology (12.3) for magnitude of interaction.

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Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)] .	With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)] .
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)] .	With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)] .
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.7)] .
Benzodiazepines (e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.7)].	Monitor sedation and blood pressure. Adjust dose accordingly.

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Digoxin concentrations increased greater than 50%
	Digoxin Serum Concentration Increase	Digoxin AUC Increase	Recommendations
Quinidine	NA	54-83%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
Ritonavir	NA	86%
Digoxin concentrations increased less than 50%
Amiodarone	17%	40%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
Propafenone	28%	29%
Quinine	NA	34-38%
Spironolactone	NA	44%
Verapamil	NA	24%

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Drug Interactions Associated With Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin	Monitor phenytoin level (7)
Methotrexate	Monitor for methotrexate toxicity (7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine (7)

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Drugs That Interfere with Hemostasis
Clinical Impact:	Oxaprozin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of oxaprozin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case- control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of oxaprozin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2) ].
Intervention:	Concomitant use of oxaprozin and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11) ]. Oxaprozin is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta- blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of oxaprozin and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of oxaprozin and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6) ].
	When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of oxaprozin with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6) ].
Digoxin
Clinical Impact:	The concomitant use of oxaprozin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of oxaprozin and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of oxaprozin and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction) because NSAID administration may result in increased plasma levels of methotrexate, especially in patients receiving high doses of methotrexate.
Intervention:	During concomitant use of oxaprozin and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of oxaprozin and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of oxaprozin and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of oxaprozin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention:	The concomitant use of oxaprozin with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of oxaprozin and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of oxaprozin and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.

Corticosteroids
Clinical Impact:	Concomitant use of corticosteroids with oxaprozin may increase the risk of GI ulceration or bleeding.
Intervention:	Monitor patients with concomitant use of oxaprozin with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)].
Glyburide
Clinical Impact:	While oxaprozin does alter the pharmacokinetics of glyburide, co-administration of oxaprozin to type II non-insulin dependent diabetic patients did not affect the area under the glucose concentration curve nor the magnitude or duration of control.
Intervention:	During concomitant use of oxaprozin and glyburide, monitor patient’s blood glucose in the beginning phase of cotherapy.

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Table 18. Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Co-administered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy-Risperidone (RatioChange relative to reference)		Risperidone Dose Recommendation
Co-administered Drug	Co-administered Drug	Risperidone	AUC	C_max
Enzyme (CYP 2D6) Inhibitors
Fluoxetine	20 mg/day	2 mg or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine	573 mg/day ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg 4 times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed

Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate[see Warnings and Precautions (5.6).]
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [see Adverse Reactions (6.1).]
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution 2-fold increase in exposure	Monitor for sildenafil toxicity (see Pharmacokinetics -(12.3)-].
Duloxetine	Avoid Use 5-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx^® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2)].	Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Table 5. Established and Other Potentially Significant Drug Interactions
↓= Decreased (induces lamotrigine glucuronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine concentrations approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine and Carbamazepine epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
	? carbamazepine epoxide.	May increase carbamazepine Epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
	? valproate	There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Figure 2: Effect of venlafaxine on the pharmacokinetics interacting drugs and their active metabolites.

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistatcontaining products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin dailyFor patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( 7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( 7)
Phenytoin	Monitor phenytoin level ( 7)
Methotrexate	Monitor for methotrexate toxicity ( 7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine ( 7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin tablets absorption. Take 2 hours before or 6 hours after ciprofloxacin tablets ( 7)

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
	? CBZ epoxide	May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 2Clinically Significant Drug Interactions with Indomethacin Drugs That Interfere with Hemostasis
Clinical Impact :	Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant uses of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention :	Monitor patients with concomitant use of indomethacin capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions ( 5 . 11)].
Aspirin
Clinical Impact :	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions ( 5 . 2)].
Intervention :	Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions ( 5 . 11)]. Indomethacin capsules are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors , Angiotensin Receptor Blockers , and Beta - Blockers
Clinical Impact :	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention :	During concomitant use of indomethacin capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of Indomethacin capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions ( 5 . 6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact :	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. It has been reported that the addition of triamterene to a maintenance schedule of Indomethacin capsules resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin capsules and triamterene should not be administered together. Both Indomethacin capsules and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin capsules and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently.
Intervention :	Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels [see Warnings and Precautions ( 5 . 6)].
Digoxin
Clinical Impact :	The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention :	During concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact :	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention :	During concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact :	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention :	During concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact :	Concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention :	During concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact :	Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions ( 5 . 2 )]. Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin. [see Clinical Pharmacology ( 12 . 3)]. In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage.
Intervention :	The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended.
Pemetrexed
Clinical Impact :	Concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention :	During concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Probenecid
Clinical Impact :	When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased.
Intervention :	During the concomitant use of indomethacin capsules and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments.

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Drugs that Affect Renal Function	A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics	Dofetilide	Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
	Sotalol	Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
	Dronedarone	Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog	Teriparatide	Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement	Thyroid	Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics	Epinephrine Norepinephrine Dopamine	Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents	Succinylcholine	May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements	Calcium	If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers		Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.
Hyperpolarization-activated cyclic nucleotide-gated channel blocker	Ivabradine	Can increase the risk of bradycardia.

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Antiretrovirals
Clinical Impact:	The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3)]. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)]. There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
Intervention:	Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications (4)]. Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:	Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention:	Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact:	Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].
Intervention:	A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact:	Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)]. There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention:	Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6)].
Citalopram
Clinical Impact:	Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention:	Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:	Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].
Intervention:	Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:	Potential for increased exposure of phenytoin.
Intervention:	Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:	Increased exposure of diazepam [see Clinical Pharmacology (12.3)].
Intervention:	Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:	Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention:	Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:	Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:	Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)]. See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:	Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated.
	Amoxicillin also has drug interactions.
Intervention:	See Contraindications, Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact:	Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention:	Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:	Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10), Clinical Pharmacology (12.2)].
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:	Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact:	There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:	An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:	There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:	Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g.,itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicstat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily*
Grapefruit juice	Avoid grapefruit juice

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1A2	2C9	3A4	2C19
Warfarin	Warfarin	Alprazolam	Omeprazole
Theophylline
Propranolol
Tizanidine

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Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	The concomitant use of SSRIs including sertraline hydrochloride and MAOIs increases the risk of serotonin syndrome.
Intervention:	Sertraline hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [See Dosage and Administration (2.5), Contraindications (4), Warnings and Precautions (5.2)].
Examples:	selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
Pimozide
Clinical Impact:	Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QT prolongation and ventricular arrhythmias.
Intervention:	Concomitant use of pimozide and sertraline hydrochloride is contraindicated [See Contraindications (4)].
Other Serotonergic Drugs
Clinical Impact:	The concomitant use of serotonergic drugs with sertraline hydrochloride increases the risk of serotonin syndrome.
Intervention:	Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of sertraline hydrochloride and/or concomitant serotonergic drugs [See Warnings and Precautions (5.2)].
Examples:	other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort
Drugs that Interfere with Hemostasis (antiplatelet agents and anticoagulants)
Clinical Impact:	The concurrent use of an antiplatelet agent or anticoagulant with sertraline hydrochloride may potentiate the risk of bleeding.
Intervention:	Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [See Warnings and Precautions (5.3)].
Examples:	aspirin, clopidogrel, heparin, warfarin
Drugs Highly Bound to Plasma Protein
Clinical Impact:	Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of sertraline hydrochloride with another drug that is highly bound to plasma protein may increase free concentrations of sertraline hydrochloride or other tightly-bound drugs in plasma [See Clinical Pharmacology (12.3)].
Intervention:	Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs as warranted.
Examples:	warfarin
Drugs Metabolized by CYP2D6
Clinical Impact:	Sertraline hydrochloride is a CYP2D6 inhibitor [See Clinical Pharmacology (12.3)]. The concomitant use of sertraline hydrochloride with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate.
Intervention:	Decrease the dosage of a CYP2D6 substrate if needed with concomitant sertraline hydrochloride use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride is discontinued.
Examples:	propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine
Phenytoin
Clinical Impact:	Phenytoin is a narrow therapeutic index drug. sertraline hydrochloride may increase phenytoin concentrations.
Intervention:	Monitor phenytoin levels when initiating or titrating sertraline hydrochloride. Reduce phenytoin dosage if needed.
Examples:	phenytoin, fosphenytoin

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Benzodiazepines
Clinical Impact:	There have been a number of reports regarding coma and death associated with the misuse and abuse of the combination of buprenorphine and benzodiazepines. In many, but not all of these cases, buprenorphine was misused by self-injection of crushed buprenorphine tablets. Preclinical studies have shown that the combination of benzodiazepines and buprenorphine altered the usual ceiling effect on buprenorphine-induced respiratory depression, making the respiratory effects of buprenorphine appear similar to those of full opioid agonists.
Intervention:	Closely monitor patients with concurrent use of buprenorphine sublingual tablets and benzodiazepines. Warn patients that it is extremely dangerous to self-administer benzodiazepines while taking buprenorphine sublingual tablets, and warn patients to use benzodiazepines concurrently with buprenorphine sublingual tablets only as directed by their healthcare provider.
Non-Benzodiazepine Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of non-benzodiazepine CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.2, 5.3)].
Examples:	Alcohol, non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids.
Inhibitors of CYP3A4
Clinical Impact:	The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of buprenorphine sublingual tablets is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease [see Clinical Pharmacology (12.3)], potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to buprenorphine.
Intervention:	If concomitant use is necessary, consider dosage reduction of buprenorphine sublingual tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the buprenorphine sublingual tablet dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples:	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact:	The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine [see Clinical Pharmacology (12.3)], potentially resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both therapeutic effects and adverse reactions and may cause serious respiratory depression.
Intervention:	If concomitant use is necessary, consider increasing the buprenorphine sublingual tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider buprenorphine sublingual tablets dosage reduction and monitor for signs of respiratory depression.
Examples:	Rifampin, carbamazepine, phenytoin
Antiretrovirals: Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Clinical Impact:	Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine, and etravirine are known CYP3A inducers, whereas delaviridine is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects.
Intervention:	Patients who are on chronic buprenorphine sublingual tablets treatment should have their dose monitored if NNRTIs are added to their treatment regimen.
Examples:	efavirenz, nevirapine, etravirine, delavirdine
Antiretrovirals: Protease inhibitors (PIs)
Clinical Impact:	Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity (atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine, and patients in one study reported increased sedation. Symptoms of opioid excess have been found in post-marketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly.
Intervention:	Monitor patients taking buprenorphine sublingual tablets and atazanavir with and without ritonavir, and reduce dose of buprenorphine sublingual tablets if warranted.
Examples:	atazanavir, ritonavir
Antiretrovirals: Nucleoside reverse transcriptase inhibitors (NRTIs)
Clinical Impact:	Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected.
Intervention:	None
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue buprenorphine sublingual tablets if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).
Intervention:	The use of buprenorphine sublingual tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Muscle Relaxants
Clinical Impact:	Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients receiving muscle relaxants and buprenorphine sublingual tablets for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of buprenorphine sublingual tablets and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when buprenorphine sublingual tablets are used concomitantly with anticholinergic drugs.

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Figure 6: Mean Standing Systolic Blood Pressure Change from Baseline

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Table 4. Drugs That May Alter Hepatic Metabolism of T4 (Hypothyroidism)
Potential impact: Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased SYNTHROID requirements.
Drug or Drug Class	Effect
Phenobarbital Rifampin	Phenobarbital has been shown to reduce the response to thyroxine. Phenobarbital increases L-thyroxine metabolism by inducing uridine 5’-diphospho-glucuronosyltransferase (UGT) and leads to a lower T4 serum levels. Changes in thyroid status may occur if barbiturates are added or withdrawn from patients being treated for hypothyroidism. Rifampin has been shown to accelerate the metabolism of levothyroxine.

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Table 6: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (C _max and AUC _τ after 200 mg q12h)	Recommendations for Voriconazole Dosage Adjustment/Comments
Rifampin^* and Rifabutin^* (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (400 mg q24h)^** (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (300 mg q24h)^** (CYP450 Induction)	Slight Decrease in AUC_τ	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)^** (CYP450 Induction)	Significantly Reduced	Contraindicated
Low-dose Ritonavir (100 mg q12h)^** (CYP450 Induction)	Reduced	Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Phenytoin^* (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John’s Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives^** containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole^** (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir
	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIs^*** (CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to voriconazole
	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Careful assessment of voriconazole effectiveness

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Table 4. Other Potentially Significant Drug Interactions
Concomitant Drug Class or Food	Noted or Anticipated Outcome	Clinical Comment
HMG-Co A Reductase Inhibitors: atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin	Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality) P-gp substrate; rhabdomyolysis has been reported	Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy.
Other Lipid-Lowering Drugs: fibrates, gemfibrozil
Digitalis Glycosides: digoxin

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AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxideIs not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.8)].
Benzodiazepines (e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.8)]	Monitor sedation and blood pressure. Adjust dose accordingly.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Bleeding times
Clinical Impact:	Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention:	This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact:	The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention:	Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact:	Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention:	This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.

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Table 12: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Drugs	Effect on Concentration	Clinical Comment
Antiretroviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs): zidovudine	↔ zidovudine	Monitor blood cell count and suppressive effect on bone marrow function when zidovudine is coadministered with PegIntron.
Immunosuppressants: e.g., cyclosporine sirolimus tacrolimus	Effect on immunosuppressants unknown	Therapeutic monitoring of the immunosuppressive agents is recommended upon coadministration with PegIntron.
Narcotic Analgesics: methadone	↑ methadone	Methadone dosage may need to be reduced when coadministered with PegIntron.
Neuroleptics: thioridazine	↑ thioridazine	Monitor for thioridazine adverse events when coadministered with PegIntron.
Xanthines: theophylline	↑ theophylline	Monitor for theophylline adverse events when coadministered with PegIntron.

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Table 4: Clinically Important Drug Interactions with VIIBRYD
Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Monoamine Oxidase Inhibitors (MAOIs)	The concomitant use of MAOIs and serotonergic drugs including VIIBRYD increases the risk of serotonin syndrome.	VIIBRYD is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Contraindications (4), Dosage and Administration (2.3), and Warnings and Precautions (5.2)].
Other Serotonergic Drugs	The concomitant use of serotonergic drugs including VIIBRYD and other serotonergic drugs increases the risk of serotonin syndrome.	Monitor patients for signs and symptoms of serotonin syndrome, particularly during VIIBRYD initiation. If serotonin syndrome occurs, consider discontinuation of VIIBRYD and/or concomitant serotonergic drugs [see Warnings and Precautions (5.2)].
Antiplatelet Agents and Anticoagulants	Serotonin release by platelets plays an important role in hemostasis. The concurrent use of an antiplatelet agent or anticoagulant with VIIBRYD may potentiate the risk of bleeding.	Inform patients of the increased risk of bleeding with the concomitant use of VIIBRYD and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio (INR) when initiating or discontinuing VIIBRYD [see Warnings and Precautions (5.3)].
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin, voriconazole)	The concomitant use of VIIBRYD and strong CYP3A4 inhibitors increased the exposure of vilazodone compared to the use of VIIBRYD alone [see Clinical Pharmacology (12.3)].	The VIIBRYD dose should not exceed 20 mg once daily with the concomitant use of a strong CYP3A4 inhibitor [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].
Strong CYP3A4 Inducers (e.g., carbamazepine, phenytoin, rifampin)	The concomitant use of VIIBRYD and strong CYP3A4 inducers decreased the exposure of vilazodone compared to the use of VIIBRYD alone [see Clinical Pharmacology (12.3)].	Based on clinical response, consider increasing the dosage of VIIBRYD, over 1 to 2 weeks in patients taking strong CYP3A4 inducers for greater than 14 days [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].
Digoxin	Digoxin is a narrow therapeutic index drug. Concomitant use of VIIBRYD increased digoxin concentrations [see Clinical Pharmacology (12.3)].	Measure serum digoxin concentrations before initiating concomitant use of VIIBRYD. Continue monitoring and reduce digoxin dose as necessary.

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Table II. Clinically significant drug interactions with theophylline Refer to PRECAUTIONS, Drug Interactions for further information regarding table. .
Drug	Type of Interaction	Effect Average effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine	Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.
Alcohol	A single large dose of alcohol (3 ml/kg of whiskey) decreases theophylline clearance for up to 24 hours.	30% increase
Allopurinol	Decreases theophylline clearance doses ≥600 mg/day.	25% increase at allopurinol
Amino glutethimide	Increases theophylline clearance by induction of microsomal enzyme activity.	25% decrease
Carbamazepine	Similar to aminoglutethimide.	30% decrease
Cimetidine	Decreases theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase
Ciprofloxacin	Similar to cimetidine.	40% increase
Clarithromycin	Similar to erythromycin.	25% decrease
Diazepam	Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.	Large diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram	Decreases theophylline clearance by inhibiting hydroxylation and demethylation.	50% increase
Enoxacin	Similar to cimetidine.	300% increase
Ephedrine	Synergistic CNS effects.	Increased frequency of nausea, nervousness, and insomnia.
Erythromycin	Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen	Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.	30% increase
Flurazepam	Similar to diazepam.	Similar to diazepam.
Fluvoxamine	Similar to cimetidine.	Similar to cimetidine.
Halothane	Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.	Increased risk of ventricular arrhythmias
Interferon, human recombinant alpha-A	Decreases theophylline clearance.	100% increase
Isoproterenol (IV)	Increases theophylline	20% decrease
Ketamine	Pharmacologic	May lower theophylline seizure threshold.
Lithium	Theophylline increases renal lithium clearance.	Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam	Similar to diazepam.	Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.	20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine	Similar to disulfiram.	80% increase
Midazolam	Similar to diazepam.	Similar to diazepam.
Moricizine	Increases theophylline clearance.	25% decrease
Pancuronium	Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.	Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifyline (PB)	Similar to aminogluethimide.	25% decrease after two weeks of concurrent PB.
Phenytoin	Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.	Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone	Decreases theophylline clearance and pharmacologic interaction.	40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and pharmacologic interaction.	100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin	Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.	20-40% decrease
Sulfinpyrazone	Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.	20% decrease
Tacrine	Similar to cimetidine, also increases renal clearance to theophylline.	90% increase
Thiabendazole	Decreases theophylline clearance.	190% increase
Ticlopidine	Decreases theophylline clearance.	60% increase
Troleandomycin	Similar to erythromycin.	33-100% increase depending on troleandomycin dose.
Verapamil	Similar to disulfiram.	20% increase

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Drugs That Increase Cyclosporine Concentrations
Calcium Channel Blockers	Antifungals	Antibiotics	Glucocorticoids	Other Drugs
diltiazem nicardipine verapamil	fluconazole itraconazole ketoconazole voriconazole	azithromycin clarithromycin erythromycin quinupristin/ dalfopristin	methylprednisolone	allopurinol amiodarone bromocriptine colchicine danazol imatinib metoclopramide nefazodoneoral contraceptives

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Drugs That Interfere with Hemostasis

Clinical Impact:

• Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone.
• Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C _max and AUC _τ)	Recommendations for Drug Dosage Adjustment/Comments
Sirolimus Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (400 mg q 24h) Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects (CYP3A4 Inhibition) Efavirenz (300 mg q 24h) (CYP3A4 Inhibition)	Significantly Increased Slight decrease in AUC _t	Contraindicated When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h) (CYP3A4 Inhibition)	No Significant Effect of Voriconazole on Ritonavir C _max or AUC _τ	Contraindicated because of significant reduction of voriconazole C _max and AUCτ
Low-dose Ritonavir (100 mg q12h)	Slight Decrease in Ritonavir C _max and AUC _τ	Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole C _max and AUC _τ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated
Cyclosporine (CYP3A4 Inhibition)	AUC _τ Significantly Increased; No Significant Effect on C _max	When initiating therapy with voriconazole in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
Methadone Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30 to 100 mg q24h) (CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [ see Drug Interactions ( 7) ]
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [ see Drug Interactions ( 7) ].
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [ see Drug Interactions ( 7) ].
NSAIDs Non-Steroidal Anti-Inflammatory Drug including ibuprofen and diclofenac (CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed. [ see Drug Interactions ( 7) ].
Tacrolimus (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with voriconazole in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)	Increased	Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	Monitor PT or other suitable anticoagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with voriconazole in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects on Indinavir Exposure	No dosage adjustment for indinavir when coadministered with voriconazole
	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIs Non-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.
Everolimus (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Concomitant administration of voriconazole and everolimus is not recommended

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Drug	Type of Interaction	Effect**
Adenosine	Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.
Alcohol	A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours.	30% increase
Allopurinol	Decreases theophylline clearance at allopurinol doses ≥600 mg/day.	25% increase
Aminoglutethimide	Increases theophylline clearance by induction of microsomal enzyme activity.	25% decrease
Carbamazepine	Similar to aminoglutethimide.	30% decrease
Cimetidine	Decreases theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase
Ciprofloxacin	Similar to cimetidine.	40% increase
Clarithromycin	Similar to erythromycin.	25% increase
Diazepam	Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.	Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram	Decreases theophylline clearance by inhibiting hydroxylation and demethylation.	50% increase
Enoxacin	Similar to cimetidine.	300% increase
Ephedrine	Synergistic CNS effects.	Increased frequency of nausea, nervousness, and insomnia.
Erythromycin	Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen	Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.	30% increase
Flurazepam	Similar to diazepam.	Similar to diazepam.
Fluvoxamine	Similar to cimetidine.	Similar to cimetidine.
Halothane	Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.	Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A	Decreases theophylline clearance.	100% increase
Isoproterenol (IV)	Increases theophylline clearance.	20% decrease
Ketamine	Pharmacologic.	May lower theophylline seizure threshold
Lithium	Theophylline increases renal lithium clearance.	Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam	Similar to diazepam.	Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.	20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine	Similar to disulfiram.	80% increase
Midazolam	Similar to diazepam.	Similar to diazepam.
Moricizine	Increases theophylline clearance.	25% decrease
Pancuronium	Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.	Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline	Decreases theophylline clearance.	30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.	25% decrease after two weeks of concurrent PB.
Phenytoin	Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.	Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone	Decreases theophylline clearance and pharmacologic interaction.	40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and pharmacologic interaction.	100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin	Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.	20-40% decrease
St. John’sWort (Hypericum Perforatum)	Decrease in theophylline plasma concentrations.	Higher doses of theophylline may be required to achieve desired effect. Stopping St. John’s Wort may result in theophylline toxicity.
Sulfinpyrazone	Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.	20% decrease
Tacrine	Similar to cimetidine, also increases renal clearance of theophylline.	90% increase
Thiabendazole	Decreases theophylline clearance.	190% increase
Ticlopidine	Decreases theophylline clearance.	60% increase
Troleandomycin	Similar to erythromycin.	33-100% increase depending on troleandomycin dose.
Verapamil	Similar to disulfiram.	20% increase

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Table III. Drugs That Have Been Documented Not to Interact With Theophylline or Drugs That Produce No Clinically Significant Interaction With Theophylline*
albuterol, systemic and inhaled amoxicillin ampicillin, with or without sulbactam atenolol azithromycin caffeine, dietary ingestion cefaclor co-trimoxazole (trimethoprim and sulfamethoxazole) diltiazem dirithromycin enflurane famotidine felodipine finasteride hydrocortisone isoflurane isoniazid isradipine influenza vaccine ketoconazole	lomefloxacin mebendazole medroxyprogesterone methylprednisolone metronidazole metoprolol nadolol nifedipine nizatidine norfloxacin ofloxacin omeprazole prednisone, prednisolone ranitidine rifabutin roxithromycin sorbitol (purgative doses do not inhibit theophylline absorption) sucralfate terbutaline, systemic terfenadine tetracycline tocainide
* Refer to PRECAUTIONS , Drug Interactions for information regarding table.

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptivepreparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin dailyFor patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T ₄ and T ₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT ₄. Continued administration results in a decrease in serum T ₄ and normal FT ₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T ₄ and T ₃ to TBG and transthyretin. An initial increase in serum FT ₄, is followed by return of FT ₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T ₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T ₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T ₄ to T ₃, leading to decreased T ₃ levels. However, serum T ₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T ₃ and T ₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T ₃ concentrations by 30% with minimal change in serum T ₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T ₃ and T ₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 3: Clinically Important Drug Interactions with Repaglinide
Gemfibrozil
Clinical Impact:	Gemfibrozil significantly increased repaglinide exposures by 8.1 fold [see Clinical Pharmacology (12.3)]
Intervention:	Do not administer repaglinide to patients receiving gemfibrozil [see Contraindications (4)].
Clopidogrel
Clinical Impact:	Clopidogrel increased repaglinide exposures by 3.9 to 5.1 fold [see Clinical Pharmacology (12.3)]
Intervention:	Avoid concomitant use of repaglinide with clopidogrel. If concomitant use can not be avoided, initiate repaglinide at 0.5 mg before each meal and do not exceed a total daily dose of 4 mg [see DOSAGE AND ADMINISTRATION (2.3)]. Increased frequency of glucose monitoring may be required during concomitant use.
Cyclosporine
Clinical Impact:	Cyclosporine increased low dose repaglinide exposures by 2.5 fold [see Clinical Pharmacology (12.3)]
Intervention:	Daily maximum repaglinide dose should be limited to 6 mg, and increased frequency of glucose monitoring may be required when repaglinide is co-administered with cyclosporine.
CYP2C8 and CYP3A4 Inhibitors
Intervention:	Repaglinide dose reductions and increased frequency of glucose monitoring may be required when co-administered.
Examples:	Drugs that are known to inhibit CYP3A4 include antifungal agents (ketoconazole, itraconazole) and antibacterial agents (clarithromycin, erythromycin). Drugs that are known to inhibit CYP2C8 include trimethoprim, gemfibrozil, montelukast, deferasirox, and clopidiogrel.
CYP2C8 and CYP3A4 Inducers
Intervention:	Repaglinide dose increases and increased frequency of glucose monitoring may be required when co-administered.
Examples:	Drugs that induce the CYP3A4 and/or 2C8 enzyme systems include rifampin, barbiturates, and carbamezapine
Drugs That May Increase the Risk of Hypoglycemia
Intervention:	Repaglinide dose reductions and increased frequency of glucose monitoring may be required when co-administered.
Examples:	Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, nonsteroidal anti-inflammatory agents (NSAIDs), pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics
Drugs That May Decrease the Blood Glucose Lowering Effect of Repaglinide
Intervention:	Repaglinide dose increases and increased frequency of glucose monitoring may be required when co-administered.
Examples:	Atypical antipsychotics (e.g., olanzapine and clozapine), calcium channel antagonists, corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones.
Drugs That May Blunt Signs and Symptoms of Hypoglycemia
Intervention:	Increased frequency of glucose monitoring may be required when repaglinide is co-administered with these drugs.
Examples:	beta-blockers, clonidine, guanethidine, and reserpine

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin	Monitor phenytoin level (7)
Methotrexate	Monitor for methotrexate toxicity (7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)

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Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.6).]
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported . Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [see Adverse Reactions (6.1).]
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution 2-fold increase in exposure	Monitor for sildenafil toxicity (see Pharmacokinetics -(12.3)-] .
Duloxetine	Avoid Use 5-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx ^® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2)].	Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir )	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Dosage adjustment due to drug interactions (7.1):
Factors	Dosage Adjustments for Aripiprazole
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors	Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double usual dose over 1 to 2 weeks

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Table 2. Drug Interactions: Pharmacokinetic Parameters for Azithromycin in the Presence of Coadministered Drugs (see PRECAUTIONS, Drug Interactions).
NA – Not available ^* - 90% Confidence interval not reported Mean azithromycin concentrations one day after the last dose were 53 ng/mL when coadministered with 300 mg daily rifabutin and 49 ng/mL when coadministered with placebo.
Coadministered Drug	Dose of Coadministered Drug	Dose of Azithromycin	n	Ratio (with/without coadministered drug) of Azithromycin Pharmacokinetic Parameters (90% CI); No Effect = 1.00
Coadministered Drug	Dose of Coadministered Drug	Dose of Azithromycin	n	Mean C_max	Mean AUC
Efavirenz	400 mg/day x 7 days	600 mg PO on day 7	14	1.22 (1.04 to 1.42)	0.92^*
Fluconazole	200 mg PO single dose	1,200 mg PO single dose	18	0.82 (0.66 to 1.02)	1.07 (0.94 to 1.22)
Nelfinavir	750 mg TID x 11 days	1,200 mg PO on day 9	14	2.36 (1.77 to 3.15)	2.12 (1.80 to 2.50)
Rifabutin	300 mg/day x 10 days	500 mg PO on day 1, then 250 mg/day on days 2 to 10	6	See footnote below	NA

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Table 5. Clinically-Significant Drug Interactions with Sertraline Hydrochloride
Monoamine Oxidase Inhibitors ( MAOIs )
Clinical Impact :	The concomitant use of SSRIs including sertraline hydrochloride and MAOIs increases the risk of serotonin syndrome.
Intervention :	Sertraline hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [ See Dosage and Administration ( 2 . 5 ), Contraindications ( 4 ), Warnings and Precautions ( 5 . 2)].
Examples :	selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
Pimozide
Clinical Impact :	Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QT prolongation and ventricular arrhythmias.
Intervention :	Concomitant use of pimozide and sertraline hydrochloride is contraindicated [ See Contraindications ( 4)].
Other Serotonergic Drugs
Clinical Impact :	The concomitant use of serotonergic drugs with sertraline hydrochloride increases the risk of serotonin syndrome.
Intervention :	Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of sertraline hydrochloride and/or concomitant serotonergic drugs [ See Warnings and Precautions ( 5 . 2)].
Examples :	other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort
Drugs that Interfere with Hemostasis ( antiplatelet agents and anticoagulants )
Clinical Impact :	The concurrent use of an antiplatelet agent or anticoagulant with sertraline hydrochloride may potentiate the risk of bleeding.
Intervention :	Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [ See Warnings and Precautions ( 5 . 3)].
Examples :	aspirin, clopidogrel, heparin, warfarin
Drugs Highly Bound to Plasma Protein
Clinical Impact :	Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of sertraline hydrochloride with another drug that is highly bound to plasma protein may increase free concentrations of sertraline hydrochloride or other tightly-bound drugs in plasma [ See Clinical Pharmacology ( 12 . 3 )].
Intervention :	Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs as warranted.
Examples :	warfarin
Drugs Metabolized by CYP2D6
Clinical Impact :	Sertraline hydrochloride is a CYP2D6 inhibitor [ See Clinical Pharmacology ( 12 . 3)]. The concomitant use of sertraline hydrochloride with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate.
Intervention :	Decrease the dosage of a CYP2D6 substrate if needed with concomitant sertraline hydrochloride use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride is discontinued.
Examples :	propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine
Phenytoin
Clinical Impact :	Phenytoin is a narrow therapeutic index drug. Sertraline hydrochloride may increase phenytoin concentrations.
Intervention :	Monitor phenytoin levels when initiating or titrating sertraline hydrochloride. Reduce phenytoin dosage if needed.
Examples :	phenytoin, fosphenytoin

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.12, 7.3)

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Table 2: Drug — Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion -the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥100 mg/day or equivalent); Octreotide (>100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport — but FT₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone > 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.

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Table 6: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
^ Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects ^ Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects *** Non-Nucleoside Reverse Transcriptase Inhibitors
Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (C_max and AUC _τ after 200 mg q12h)	Recommendations for Voriconazole Dosage Adjustment/Comments
Rifampin^* and Rifabutin^* (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (400 mg q24h)^ (CYP450 Induction) Efavirenz (300 mg q24h)^ (CYP450 Induction)	Significantly Reduced Slight Decrease in AUC _τ	Contraindicated When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)^ (CYP450 Induction) Low-dose Ritonavir (100 mg q12h)^ (CYP450 Induction)	Significantly Reduced Reduced	Contraindicated Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Phenytoin^* (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John’s Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives^** containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole^** (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIs^*** (CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure) A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to voriconazole Careful assessment of voriconazole effectiveness

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Inhibitors of CYP2D6
Clinical Impact:	The concomitant use of tramadol hydrochloride extended-release tablets and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride extended-release tablets is achieved. Since M1 is a more potent μ-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease and the M1 plasma concentration will increase which could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, and may cause potentially fatal respiratory depression [see Clinical Pharmacology (12.3)].
Intervention:	If concomitant use of a CYP2D6 inhibitor is necessary, follow patients closely for adverse reactions including opioid withdrawal, seizures, and serotonin syndrome. If a CYP2D6 inhibitor is discontinued, consider lowering tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved. Follow patients closely for adverse events including respiratory depression and sedation.
Examples	Quinidine, fluoxetine, paroxetine and bupropion
Inhibitors of CYP3A4
Clinical Impact:	The concomitant use of tramadol hydrochloride extended-release tablets and CYP3A4 inhibitors can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1. Follow patients closely for increased risk of serious adverse events including seizures and serotonin syndrome, and adverse reactions related to opioid toxicity including potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride extended-release tablets is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy and possibly signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol.
Intervention:	If concomitant use is necessary, consider dosage reduction of tramadol hydrochloride extended-release tablets until stable drug effects are achieved. Follow patients closely for seizures and serotonin syndrome, and signs of respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved and follow patients for signs and symptoms of opioid withdrawal.
Examples	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact:	The concomitant use of tramadol hydrochloride extended-release tablets and CYP3A4 inducers can decrease the plasma concentration of tramadol [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol, [see Warnings and Precautions (5.5)]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause seizures and serotonin syndrome, and potentially fatal respiratory depression.
Intervention:	If concomitant use is necessary, consider increasing the tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved. Follow patients for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider tramadol hydrochloride extended-release tablets dosage reduction and monitor for seizures and serotonin syndrome, and signs of sedation and respiratory depression. Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of tramadol hydrochloride extended-release tablets and carbamazepine is not recommended.
Examples:	Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.6)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue tramadol hydrochloride extended-release tablets if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.7)] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
Intervention:	Do not use tramadol hydrochloride extended-release tablets in patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of tramadol hydrochloride extended-release tablets and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Tramadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of tramadol hydrochloride extended-release tablets and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when tramadol hydrochloride extended-release tablets is used concomitantly with anticholinergic drugs.
Digoxin
Clinical Impact:	Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity.
Intervention:	Follow patients for signs of digoxin toxicity and adjust the dosage of digoxin as needed.
Warfarin
Clinical Impact:	Post-marketing surveillance of tramadol has revealed rare reports of alteration of warfarin effect, including elevation of prothrombin times.
Intervention:	Monitor the prothrombin time of patients on warfarin for signs of an interaction and adjust the dosage of warfarin as needed.

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Table 4 Other Potentially Significant Drug Interactions
Concomitant Drug Class or Food	Noted or Anticipated Outcome	Clinical Comment
HMG-Co A Reductase Inhibitors: atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin	Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality)	Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy.
Other Lipid Lowering Drugs: fibrates, gemfibrozil
Digitalis Glycosides: digoxin	P-gp substrate; rhabdomyolysis has been reported

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Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Drugs That Interfere with Hemostasis
Clinical Impact:	Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of naproxen with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention:	Concomitant use of naproxen and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Naproxen are not substitutes for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of naproxen and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of naproxen and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin
Intervention:	During concomitant use of naproxen and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of naproxen and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen is not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxen is not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:	Patients simultaneously receiving naproxen and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

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Drugs That Are Affected By Clarithromycin
Drug(s) with Pharmacokinetics Affected by Clarithromycin	Recommendation	Comments
Antiarrhythmics: Disopyramide Quinidine Dofetilide Amiodarone Sotalol Procainamide	Not Recommended	Disopyramide, Quinidine: There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs [see Warnings and Precautions (5.3)]. Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine. There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.
Digoxin	Use With Caution	Digoxin: Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are co administered, inhibition of Pgp by clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range.
Oral Anticoagulants: Warfarin	Use With Caution	Oral anticoagulants: Spontaneous reports in the postmarketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously [see Warnings and Precautions (5.4)].
Antiepileptics: Carbamazepine	Use With Caution	Carbamazepine: Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered. Increased serum concentrations of carbamazepine were observed in clinical trials with clarithromycin. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with carbamazepine.
Antifungals: Itraconazole	Use With Caution	Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly (see also Itraconazole under "Drugs That Affect clarithromycin" in the table below). Clarithromycin may increase the plasma concentrations of itraconazole. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions.
Fluconazole	No Dose Adjustment	Fluconazole: [see Pharmacokinetics (12.3)]
Anti-Gout Agents: Colchicine (in patients with renal or hepatic impairment) Colchicine (in patients with normal renal or hepatic function)	Contraindicated Use With Caution	Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. The dose of colchicine should be reduced when co-administered with clarithromycin in patients with normal renal and hepatic function [see Contraindications (4.4) and Warnings and Precautions (5.4)].
Antipsychotics: Pimozide Quetiapine	Contraindicated	Pimozide: [See Contraindications (4.2)] Qutiapine: Quetiapine is a substrate for CYP3A4, which is inhibited by clarithromycin. Co-administration with clarithromycin could result in increased quetiapine exposure and possible quetiapine related toxicities. There have been postmarketing reports of somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation during concomitant administration. Refer to quetiapine prescribing information for recommendations on dose reduction if co- administered with CYP3A4 inhibitors such as clarithromycin. [See Contraindications (4.2)]
Antispasmodics: Tolterodine (patients deficient in CYP2D6 activity)	Use With Caution	Tolterodine: The primary route of metabolism for tolterodine is via CYP2D6. However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when co-administered with clarithromycin.
Antivirals: Atazanavir	Use With Caution	Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under "Drugs That Affect clarithromycin" in the table below) [see Pharmacokinetics (12.3)].
Saquinavir (in patients with decreased renal function)		Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction (see Saquinavir under "Drugs That Affect clarithromycin" in the table below) [see Pharmacokinetics (12.3)].
Ritonavir Etravirine		Ritonavir, Etravirine: (see Ritonavir and Etravirine under "Drugs That Affect clarithromycin" in the table below) [see Pharmacokinetics (12.3)].
Maraviroc		Maraviroc: Clarithromycin may result in increases in maraviroc exposures by inhibition of CYP3A metabolism. See Selzentry® prescribing information for dose recommendation when given with strong CYP3A inhibitors such as clarithromycin.
Boceprevir (in patients with normal renal function) Didanosine	No Dose Adjustment	Boceprevir: Both clarithromycin and boceprevir are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when co- administered. No dose adjustments are necessary for patients with normal renal function (see Victrelis® prescribing information).
Zidovudine		Zidovudine: Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Administration of clarithromycin and zidovudine should be separated by at least two hours [see Pharmacokinetics (12.3)]. The impact of co-administration of clarithromycin extended-release tablets and zidovudine has not been evaluated.
Calcium Channel Blockers: Verapamil	Use With Caution	Verapamil: Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, [see Warnings and Precautions (5.4)].
Amlodipine Diltiazem		Amlodipine, Diltiazem: [See Warnings and Precautions (5.4)]
Nifedipine		Nifedipine: Nifedipine is a substrate for CYP3A. Clarithromycin and other macrolides are known to inhibit CYP3A. There is potential of CYP3A-mediated interaction between nifedipine and clarithromycin. Hypotension and peripheral edema were observed when clarithromycin was taken concomitantly with nifedipine [see Warnings and Precautions (5.4)].
Ergot Alkaloids: Ergotamine Dihydroergotamine	Contraindicated	Ergotamine, Dihydroergotamine: Postmarketing reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4.6)].
Gastroprokinetic Agents: Cisapride	Contraindicated	Cisapride: [See Contraindications (4.2)]
HMG-CoA Reductase Inhibitors: Lovastatin Simvastatin	Contraindicated	Lovastatin, Simvastatin, Atorvastatin, Pravastatin, Fluvastatin: [See Contraindications (4.5) and Warnings and Precautions (5.4)]
Atorvastatin Pravastatin	Use With Caution
Fluvastatin	No Dose Adjustment
Hypoglycemic Agents: Nateglinide Pioglitazone Repaglinide Rosiglitazone	Use With Caution	Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]
Insulin		Insulin: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]
Immunosuppressants: Cyclosporine	Use With Caution	Cyclosporine: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine.
Tacrolimus		Tacrolimus: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with tacrolimus.
Phosphodiesterase inhibitors: Sildenafil Tadalafil Vardenafil	Use With Caution	Sildenafil, Tadalafil, Vardenafil: Each of these phosphodiesterase inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant administration of clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil, or vardenafil will result in increased exposure of these phosphodiesterase inhibitors. Co-administration of these phosphodiesterase inhibitors with clarithromycin is not recommended. Increased systemic exposure of these drugs may occur with clarithromycin; reduction of dosage for phosphodiesterase inhibitors should be considered (see their respective prescribing information).
Proton Pump Inhibitors: Omeprazole	No Dose Adjustment	Omeprazole: The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when coadministered with clarithromycin as a result of increased omeprazole exposures [see Pharmacokinetics (12.3)] (see also Omeprazole under "Drugs That Affect clarithromycin" in the table below).
Xanthine Derivatives: Theophylline	Use With Caution	Theophylline: Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations [see Pharmacokinetics (12.3)]. Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range.
Triazolobenzodiazepines and Other Related Benzodiazepines: Midazolam	Use With Caution	Midazolam: When oral midazolam is co-administered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated [see Warnings and Precautions (5.4) and Pharmacokinetics (12.3)].
Alprazolam Triazolam		Triazolam, Alprazolam: Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is co-administered with clarithromycin. There have been postmarketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested. In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines.
Temazepam Nitrazepam Lorazepam	No Dose Adjustment	Temazepam, Nitrazepam, Lorazepam: For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.
Cytochrome P450 Inducers: Rifabutin	Use With Caution	Rifabutin: Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis (see Rifabutin under "Drugs That Affect clarithromycin" in the table below).
Other Drugs Metabolized by CYP3A: Alfentanil Bromocriptine Cilostazol Methylprednisole Vinblastine Phenobarbital St. John’s Wort	Use With Caution	There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort.
Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A: Hexobarbital Phenytoin Valproate	Use With Caution	There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.
Drugs that Affect Clarithromycin
Drug(s) that Affect the Pharmacokinetics of Clarithromycin	Recommendation	Comments
Antifungals: Itraconazole	Use With Caution	Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions (see also Itraconazole under "Drugs That Are Affected By clarithromycin" in the table above).
Antivirals: Atazanavir	Use With Caution	Atazanavir: When clarithromycin is co-administered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology (12.3)]. Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co- administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex. Doses of clarithromycin greater than 1,000 mg per day should not be co-administered with protease inhibitors.
Ritonavir (in patients with decreased renal function) Saquinavir (in patients with decreased renal function)		Ritonavir: Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with ritonavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium [see Pharmacokinetics (12.3)]. Doses of clarithromycin greater than 1,000 mg per day should not be co-administered with protease inhibitors. Saquinavir: When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (refer to ritonavir above) [see Pharmacokinetics (12.3)].
Etravirine		Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.
Saquinavir (in patients with normal renal function) Ritonavir (in patients with normal renal function)	No Dose Adjustment
Proton Pump Inhibitors: Omeprazole	Use With Caution	Omeprazole: Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole [see Pharmacokinetics (12.3)].
Miscellaneous Cytochrome P450 Inducers: Efavirenz Nevirapine Rifampicin Rifabutin Rifapentine	Use With Caution	Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under "Drugs That Are Affected By clarithromycin" in the table above).

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Table 1: Drugs that may have their plasma concentrations increased by itraconazole
Drug Class	Contraindicated	Not Recommended	Use with Caution	Comments
	Under no circumstances is the drug to be coadministered with itraconazole, and up to two weeks after discontinuation of treatment with itraconazole.	It is recommended that the use of the drug be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If coadministration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of the interacting drug is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured. The label of the coadministered drug should be consulted for information on dose adjustment and adverse effects.	Careful monitoring is recommended when the drug is coadministered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of the interacting drug, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured. The label of the coadministered drug should be consulted for information on dose adjustment and adverse effects.
Alpha Blockers		tamsulosin
Analgesics	methadone		alfentanil, buprenorphine IV and sublingual, fentanyl, oxycodone, sufentanil	Methadone: The potential increase in plasma concentrations of methadone when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation and torsade de pointes.
				Fentanyl: The potential increase in plasma concentrations of fentanyl when coadministered with itraconazole may increase the risk of potentially fatal respiratory depression.
				Sufentanil: No human pharmacokinetic data of an interaction with itraconazole are available. In vitro data suggest that sufentanil is metabolized by CYP3A4 and so potentially increased sufentanil plasma concentrations would be expected when coadministered with itraconazole.
Antiarrhythmics	disopyramide, dofetilide, dronedarone, quinidine		digoxin	Disopyramide, dofetilide, dronedarone, quinidine: The potential increase in plasma concentrations of these drugs when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation.
Antibacterials	telithromycin, in subjects with severe renal impairment or severe hepatic impairment	rifabutin	telithromycin	Telithromycin: The potential increase in plasma concentrations of telithromycin in subjects with severe renal impairment or severe hepatic impairment, when coadministered with itraconazole may increase the risk of serious cardiovascular events including QT prolongation and torsade de pointes.
				Rifabutin: See also under ' Drugs that may decrease itraconazole plasma concentrations'.
Anticoagulants and Antiplatelet Drugs	ticagrelor	apixaban, rivaroxaban	coumarins, cilostazol, dabigatran	Ticagrelor: The potential increase in plasma concentrations of ticagrelor may increase the risk of bleeding.
				Coumarins: Itraconazole may enhance the anticoagulant effect of coumarin-like drugs, such as warfarin.
Anticonvulsants		carbamazepine		Carbamazepine: In vivo studies have demonstrated an increase in plasma carbamazepine concentrations in subjects concomitantly receiving ketoconazole. Although there are no data regarding the effect of itraconazole on carbamazepine metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of itraconazole and carbamazepine may inhibit the metabolism of carbamazepine. See also under ' Drugs that may decrease itraconazole plasma concentrations'.
Antidiabetics			repaglinide, saxagliptin
Antihelmintics and Antiprotozoals			praziquantel
Antimigraine Drugs	ergot alkaloids, such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine)		eletriptan	Ergot Alkaloids: The potential increase in plasma concentrations of ergot alkaloids when coadministered with itraconazole may increase the risk of ergotism, ie. a risk for vasospasm potentially leading to cerebral ischemia and/or ischemia of the extremities.
Antineoplastics	irinotecan	axitinib, dabrafenib, dasatinib, ibrutinib, nilotinib, sunitinib, trabectedin	bortezomib, busulphan, docetaxel, erlotinib, gefitinib, imatinib, ixabepilone, lapatinib, ponatinib, trimetrexate, vinca alkaloids	Irinotecan: The potential increase in plasma concentrations of irinotecan when coadministered with itraconazole may increase the risk of potentially fatal adverse events.
Antipsychotics, Anxiolytics and Hypnotics	lurasidone, oral midazolam, pimozide, triazolam		alprazolam, aripiprazole, buspirone, diazepam, haloperidol, midazolam IV, perospirone, quetiapine, ramelteon, risperidone	Midazolam, triazolam: Coadministration of itraconazole and oral midazolam, or triazolam may cause several-fold increases in plasma concentrations of these drugs. This may potentiate and prolong hypnotic and sedative effects, especially with repeated dosing or chronic administration of these agents.
				Pimozide: The potential increase in plasma concentrations of pimozide when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation and torsade de pointes.
Antivirals		simeprevir	maraviroc, indinavir, ritonavir, saquinavir	Indinavir, ritonavir: See also under ' Drugs that may increase itraconazole plasma concentrations'.
Beta Blockers			nadolol
Calcium Channel Blockers	felodipine, nisoldipine		other dihydropyridines, verapamil	Calcium channel blockers can have a negative inotropic effect which may be additive to those of itraconazole. The potential increase in plasma concentrations of calcium channel blockers when co-administered with itraconazole may increase the risk of congestive heart failure. Dihydropyridines: Concomitant administration of itraconazole may cause several-fold increases in plasma concentrations of dihydropyridines. Edema has been reported in patients concomitantly receiving itraconazole and dihydropyridine calcium channel blockers.
Cardiovascular Drugs, Miscellaneous	Ivabradine, ranolazine	aliskiren, sildenafil, for the treatment of pulmonary hypertension	bosentan, riociguat	Ivabradine: The potential increase in plasma concentrations of ivabradine when coadministered with itraconazole may increase the risk of ivabradine-related adverse events, such as atrial fibrillation, bradycardia, sinus arrest and heart block. Ranolazine: The potential increase in plasma concentrations of ranolazine when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation.
Diuretics	eplerenone			Eplerenone: The potential increase in plasma concentrations of eplerenone when coadministered with itraconazole may increase the risk of hyperkalemia and hypotension.
Gastrointestinal Drugs	cisapride		aprepitant	Cisapride: The potential increase in plasma concentrations of cisapride when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation.
Immunosuppressants		everolimus, temsirolimus	budesonide, ciclesonide, cyclosporine, dexamethasone, fluticasone, methylprednisolone, rapamycin (also known as sirolimus), tacrolimus
Lipid Regulating Drugs	lovastatin, simvastatin		atorvastatin	The potential increase in plasma concentrations of atorvastatin, lovastatin, and simvastatin when coadministered with itraconazole may increase the risk of skeletal muscle toxicity, including rhabdomyolysis.
Respiratory Drugs		salmeterol
Urological Drugs	fesoterodine, in subjects with moderate to severe renal impairment, or moderate to severe hepatic impairment, solifenacin, in subjects with severe renal impairment or moderate to severe hepatic impairment	darifenacin, vardenafil	fesoterodine. oxybutynin, sildenafil, for the treatment of erectile dysfunction, solifenacin, tadalafil, tolterodine	Fesoterodine: The potential increase in plasma concentrations of the fesoterodine active metabolite may be greater in subjects with moderate to severe renal impairment, or moderate to severe hepatic impairment, which may lead to an increased risk of adverse reactions. Solifenacin: The potential increase in plasma concentrations of solifenacin in subjects with severe renal impairment or moderate to severe hepatic impairment, when coadministered with itraconazole may increase the risk of serious cardiovascular events including QT prolongation.
Other	colchicine, in subjects with renal or hepatic impairment	colchicine, conivaptan, tolvaptan	cinacalcet	Colchicine: The potential increase in plasma concentrations of colchicine when coadministered with itraconazole may increase the risk of potentially fatal adverse events.
				Conivaptan and Tolvaptan: A safe and effective dose of either conivaptan or tolvaptan has not been established when coadministered with itraconazole.

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Substance	Average Duration of Effect
Anti-thyroid drugs e.g., carbimazole, propylthiouracil	5 days
Natural or synthetic thyroid hormone e.g., thyroxine tri-iodothyronine	4 weeks 2 weeks
Iodine-containing medications e.g., amiodarone expectorants, vitamins	4 weeks 2 weeks
Topical iodide	1-9 months
X-ray contrast agents iodine-containing agents	Up to 1 year
Other drugs anticoagulants, antihistamines corticosteroids, sulfonamides tolbutamide, perchlorate phenylbutazone lithium	1 week 1 week 1 week 1-2 weeks 4 weeks

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Table 3Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate[see Warnings and Precautions (5.6).]
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [see Adverse Reactions (6.1).]
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution 2-fold increase in exposure	Monitor for sildenafil toxicity (see Pharmacokinetics -(12.3)-].
Duloxetine	Avoid Use 5-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx^® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2)].	Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

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Classes of Drugs
5-lipoxygenase Inhibitor Adrenergic Stimulants, Central Alcohol Abuse Reduction Preparations Analgesics Anesthetics, Inhalation Antiandrogen Antiarrhythmics† Antibiotics† Aminoglycosides (oral) Cephalosporins, parenteral Macrolides Miscellaneous Penicillins, intravenous, high dose Quinolones (fluoroquinolones) Sulfonamides, long acting Tetracyclines Anticoagulants Anticonvulsants† Antidepressants† Antimalarial Agents Antineoplastics† Antiparasitic/Antimicrobials	Antiplatelet Drugs/Effects Antithyroid Drugs† Beta-Adrenergic Blockers Cholelitholytic Agents Diabetes Agents, Oral Diuretics† Fungal Medications, Intravaginal, Systemic† Gastric Acidity and Peptic Ulcer Agents† Gastrointestinal Prokinetic Agents Ulcerative Colitis Agents Gout Treatment Agents Hemorrheologic Agents Hepatotoxic Drugs Hyperglycemic Agents Hypertensive Emergency Agents Hypnotics† Hypolipidemics† Bile Acid-Binding Resins† Fibric Acid Derivatives HMG-CoA Reductase Inhibitors†	Leukotriene Receptor Antagonist Monoamine Oxidase Inhibitors Narcotics, prolonged Nonsteroidal Anti- Inflammatory Agents Proton Pump Inhibitors Psychostimulants Pyrazolones Salicylates Selective Serotonin Reuptake Inhibitors Steroids, Adrenocortical† Steroids, Anabolic (17-Alkyl Testosterone Derivatives) Thrombolytics Thyroid Drugs Tuberculosis Agents† Uricosuric Agents Vaccines Vitamins†

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Table 1: Clinically Significant Drug Interactions with Morphine Sulfate Extended-Release
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)].
Examples:	Benzodiazepines and other sedative hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue morphine sulfate extended-release if serotonin syndrome is suspected.
Example:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.6)].
Intervention:	Do not use morphine sulfate extended-release in patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of morphine sulfate extended-release and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of morphine sulfate extended-release and/or the muscle relaxant as necessary.
Cimetidine
Clinical Impact:	The concomitant use of cimetidine can potentiate morphine effects and increase risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of morphine sulfate extended-release and/or cimetidine as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when morphine sulfate extended-release is used concomitantly with anticholinergic drugs.
P-Glycoprotein (P-gp) Inhibitors
Clinical Impact:	The concomitant use of PGP-inhibitors can increase the exposure to morphine by about two-fold and can increase risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of morphine sulfate extended-release and/or the PGP-inhibitor as necessary.
Example:	quinidine

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Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
*Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	Cmax
Enzyme (CYP2D6)inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not Needed

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.12, 7.3)

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T ₄ and T ₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT ₄. Continued administration results in a decrease in serum T ₄ and normal FT ₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T ₄ and T ₃ to TBG and transthyretin. An initial increase in serum FT ₄, is followed by return of FT ₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T ₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T ₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T ₄ to T ₃, leading to decreased T ₃ levels. However, serum T ₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T ₃ and T ₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T ₃ concentrations by 30% with minimal change in serum T ₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T ₃ and T ₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 7 Summary of AED Interactions with Oxcarbazepine
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400 to 2000	900	nc¹	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100 to 150	600 to 1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250 to 500	600 to 1800 >1200 to 2400	nc^1,2 up to 40% increase³ [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400 to 2800	600 to 1800	nc¹	18% decrease [CI: 13% decrease, 40% decrease]

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Drugs That Interfere with Hemostasis
Clinical Impact:		• Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:		Monitor patients with concomitant use of VOLTAREN ^® GEL with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions ( 5.11)].
Aspirin
Clinical Impact:		Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions ( 5.2)].
Intervention:		Concomitant use of VOLTAREN ^® GEL and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions ( 5.11)]. VOLTAREN ^® GEL is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:		• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:		• During concomitant use of VOLTAREN ^® GEL and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of VOLTAREN ^® GEL and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions ( 5.6)]. •When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter .
Diuretics
Clinical Impact:		Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:		During concomitant use of VOLTAREN ^® GEL with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see Warnings and Precautions ( 5.6)].
Digoxin
Clinical Impact:		The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:		During concomitant use of VOLTAREN ^® GEL and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:		NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:		During concomitant use of VOLTAREN ^® GEL and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:		Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:		During concomitant use of VOLTAREN ^® GEL and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:		Concomitant use of VOLTAREN ^® GEL and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention:		During concomitant use of VOLTAREN ^® GEL and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:		Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions ( 5.2)].
Intervention:		The concomitant use of diclofenac with other NSAIDs or salicylates is notrecommended.
Pemetrexed
Clinical Impact:		Concomitant use of VOLTAREN ^® GEL and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:		During concomitant use of VOLTAREN ^® GEL and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and Gl toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 2: Rifabutin Interaction Studies
↑ indicates increase; ↓ indicates decrease; ↔ indicates no significant change
QD-once daily; BID-twice daily; TID – thrice daily
ND -No Data
AUC -Area under the Concentration vs. Time Curve; C_m _a _x -Maximum serum concentration
^a compared to rifabutin 300 mg QD alone
^b compared to historical control (fosamprenavir/ritonavir 700/100 mg BID)
^c also taking zidovudine 500 mg QD
^d compared to rifabutin 150 mg QD alone
^e compared to rifabutin 300 mg QD alone
^f data from a case report
^g compared to voriconazole 200 mg BID alone
Coadministered drug	Dosing regimen of coadministered drug	Dosing regimen of rifabutin	Study population ( n )	Effect on rifabutin	Effect on coadministered drug	Recommendation
ANTIVIRALS
Amprenavir	1200 mg BID x 10 days	300 mg QD x 10 days	Healthy male subjects (6)	↑ AUC by 193%, ↑ C_m _a _x by 119%	↔	Reduce rifabutin dose by at least 50%. Monitor closely for adverse reactions.
Delavirdine	400 mg TID	300 mg QD	HIV-infected patients (7)	↑ AUC by 230%, ↑ C_m _a _x by 128%	↓ AUC by 80%, ↓ Cmax by 75%, ↓ C_m _i _n by 17%	CONTRAINDICATED
Didanosine	167 or 250 mg BID x 12 days	300 or 600 mg QD x 1	HIV-infected patients (11)	↔	↔
Fosamprenavir/ ritonavir	700 mg BID plus ritonavir 100 mg BID x 2 weeks	150 mg every other day x 2 weeks	Healthy subjects (15)	↔ AUC^a ↓ C_m _a _x by 15%	↑ AUC by 35%^b, ↑ C_m _a _x by 36%, ↑ C_m _i _n by 36%	Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with fosamprenavir/ritonavir combination.
Indinavir	800 mg TID x 10 days	300 mg QD x 10 days	Healthy subjects (10)	↑ AUC by 173%, ↑ Cmax by 134%	↓ AUC by 34%, ↓ C_m _a _x by 25%, ↓ C_m _i _n by 39%	Reduce rifabutin dose by 50%, and increase indinavir dose from 800 mg to 1000 mg TID.
Lopinavir/ ritonavir	400/100 mg BID x 20 days	150 mg QD x 10 days	Healthy subjects (14)	↑ AUC by 203%^c ↓ C_m _a _x by 112%	↔	Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed.
Saquinavir/ ritonavir	1000/100 mg BID x 14 or 22 days	150 mg every 3 days X 21 to 22 days	Healthy subjects	↑ AUC by 53% ^d ↑ C_m _a _x by 88% (n=11)	↓ AUC by 13%, ↓ C_m _a _x by 15%, (n=19)	Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with saquinavir/ritonavir combination. Monitor closely for adverse reactions.
Ritonavir	500 mg BID x 10 days	150 mg QD x 16 days	Healthy subjects (5)	↑ AUC by 300%, ↑ C_m _a _x by 150%	ND	Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed.
Tipranavir/ ritonavir	500/200 BID X 15 doses	150 mg single dose	Healthy subjects (20)	↑ AUC by 190%, ↑ C_m _a _x by 70%	↔	Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with tipranavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed.
Nelfinavir	1250 mg BID x 7 to 8 days	150 mg QD x 8 days	HIV-infected patients (11)	↑ AUC by 83%,^e ↑ C_m _a _x by 19%	↔	Reduce rifabutin dose by 50% (to 150 mg QD) and increase the nelfinavir dose to 1250 mg BID
Zidovudine	100 or 200 mg q4h	300 or 450 mg QD	HIV-infected patients (16)	↔	↓ AUC by 32%, ↓ C_m _a _x by 48%	Because zidovudine levels remained within the therapeutic range during coadministration of rifabutin, dosage adjustments are not necessary.
ANTIFUNGALS
Fluconazole	200 mg QD x 2 weeks	300 mg QD x 2 weeks	HIV-infected patients (12)	↑ AUC by 82%, ↑ C_m _a _x by 88%	↔	Monitor for rifabutin associated adverse events. Reduce rifabutin dose or suspend rifabutin use if toxicity is suspected.
Posaconazole	200 mg QD x 10 days	300 mg QD x 17 days	Healthy subjects (8)	↑ AUC by 72%, ↑ C_m _a _x by 31%	↓ AUC by 49%, ↓ C_m _a _x by 43%	If co-administration of these two drugs cannot be avoided, patients should be monitored for adverse events associated with rifabutin administration, and lack of posaconazole efficacy.
Itraconazole	200 mg QD	300 mg QD	HIV-Infected patients (6)	↑^f	↓ AUC by 70%, ↓ C_m _a _x by 75%	If co-administration of these two drugs cannot be avoided, patients should be monitored for adverse events associated with rifabutin administration, and lack of itraconazole efficacy. In a separate study, one case of uveitis was associated with increased serum rifabutin levels following coadministration of rifabutin (300 mg QD) with itraconazole (600 to 900 mg QD).
Voriconazole	400 mg BID x 7 days (maintenance dose)	300 mg QD x 7 days	Healthy male subjects (12)	↑ AUC by 331%, ↑ C_m _a _x by 195%	↑ AUC by ~100%, ↑ C_m _a _x by ~100%^g	CONTRAINDICATED
ANTI - PCP ( Pneumocystis carinii pneumonia )
Dapsone	50 mg QD	300 mg QD	HIV-infected patients (16)	ND	↓ AUC by 27 to 40%
Sulfamethoxazole-Trimethoprim	800/160 mg	300 mg QD	HIV-infected patients (12)	↔	↓ AUC by 15 to 20%
ANTI - MAC ( Mycobacterium avium intracellulare complex )
Azithromycin	500 mg QD x 1 day, then 250 mg QD x 9 days	300 mg QD	Healthy subjects (6)	↔	↔
Clarithromycin	500 mg BID	300 mg QD	HIV-infected patients (12)	↑ AUC by 75%	↓ AUC by 50%	Monitor for rifabutin associated adverse events. Reduce dose or suspend use of rifabutin if toxicity is suspected. Alternative treatment for clarithromycin should be considered when treating patients receiving rifabutin
ANTI - TB ( Tuberculosis )
Ethambutol	1200 mg	300 mg QD X 7 days	Healthy subjects (10)	ND	↔
Isoniazid	300 mg	300 mg QD X 7 days	Healthy subjects (6)	ND	↔
OTHER
Methadone	20 to 100 mg QD	300 mg QD X 13 days	HIV-infected patients (24)	ND	↔
Ethinylestradiol (EE)/ Norethindrone (NE)	35 mg EE / 1 mg NE X 21 days	300 mg QD X 10 days	Healthy female subjects (22)	ND	EE: ↓ AUC by 35%, ↓ Cmax by 20% NE: ↓ AUC by 46%	Patients should be advised to use additional or alternative methods of contraception.
Theophylline	5 mg/kg	300 mg X 14 days	Healthy subjects (11)	ND	↔

Table name:

Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C_max and AUC _τ )	Recommendations for Drug Dosage Adjustment/Comments
Sirolimus* (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin* (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (400 mg q24h) (CYP3A4 Inhibition) Efavirenz (300 mg q24h) (CYP3A4 Inhibition)	Significantly Increased Slight Increase in AUC_τ	Contraindicated When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High dose Ritonavir (400 mg q12h) (CYP3A4 Inhibition) Low dose Ritonavir (100 mg q12h)	No Significant Effect of Voriconazole on Ritonavir C_max or AUC_τ Slight Decrease in Ritonavir C_max and AUC_τ	Contraindicated because of significant reduction of voriconazole C_max and AUC_τ Coadministration of voriconazole and low dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole C_max and AUC_τ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated
Cyclosporine* (CYP3A4 Inhibition)	AUC_τ Significantly Increased; No Significant Effect on C_max	When initiating therapy with voriconazole in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary
Methadone*** (CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other long acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate associated adverse events may be necessary [see Drug Interactions (7)].
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole. A longer period for monitoring respiratory and other opiate associated adverse events may be necessary [see Drug Interactions (7)].
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate associated adverse events may be necessary [see Drug Interactions (7)].
NSAIDs**** including ibuprofen and diclofenac (CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [see Drug Interactions (7)].
Tacrolimus* (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with voriconazole in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin* (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)**	Increased	Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin* (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole* (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with voriconazole in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects on Indinavir Exposure In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	No dosage adjustment for indinavir when coadministered with voriconazole Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIs***** (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.
Everolimus (CYP3A4 Inhibition)	Not studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Concomitant administration of voriconazole and everolimus is not recommended.

Table name:

Table 3: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Indinavir (See PRECAUTIONS, Table 9 for Recommended Alterations in Dose or Regimen)
Coadministered drug	Dose of Coadministered drug (mg)	Dose of CRIXIVAN (mg)	n	Ratio (with/without CRIXIVAN) of Coadministered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00
				C_max	AUC	C_min
All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
Clarithromycin	500 twice daily, 7 days	800 three times daily, 7 days	12	1.19 (1.02, 1.39)	1.47 (1.30, 1.65)	1.97 (1.58, 2.46) n=11
Efavirenz	200 once daily, 14 days	800 three times daily, 14 days	20	No significant change	No significant change	--
Ethinyl Estradiol (ORTHO-NOVUM 1/35)Registered trademark of Ortho Pharmaceutical Corporation	35 mcg, 8 days	800 three times daily, 8 days	18	1.02 (0.96, 1.09)	1.22 (1.15, 1.30)	1.37 (1.24, 1.51)
Isoniazid	300 once daily in the morning, 8 days	800 three times daily, 8 days	11	1.34 (1.12, 1.60)	1.12 (1.03, 1.22)	1.00 (0.92, 1.08)
MethadoneStudy conducted in subjects on methadone maintenance.	20-60 once daily in the morning, 8 days	800 three times daily, 8 days	12	0.93 (0.84, 1.03)	0.96 (0.86, 1.06)	1.06 (0.94, 1.19)
Norethindrone (ORTHO-NOVUM 1/35)	1 mcg, 8 days	800 three times daily, 8 days	18	1.05 (0.95, 1.16)	1.26 (1.20, 1.31)	1.44 (1.32, 1.57)
Rifabutin ^•150 mg once daily in the morning, 11 days + indinavir compared to 300 mg once daily in the morning, 11 days alone	150 once daily in the morning, 10 days 300 once daily in the morning, 10 days	800 three times daily, 10 days 800 three times daily, 10 days	14 10	1.29 (1.05, 1.59) 2.34 (1.64, 3.35)	1.54 (1.33, 1.79) 2.73 (1.99, 3.77)	1.99 (1.71, 2.31) n=13 3.44 (2.65, 4.46) n=9
Ritonavir	100 twice daily, 14 days	800 twice daily, 14 days	10, 4Parallel group design; n for coadministered drug + indinavir, n for coadministered drug alone.	1.61 (1.13, 2.29)	1.72 (1.20, 2.48)	1.62 (0.93, 2.85)
	200 twice daily, 14 days	800 twice daily, 14 days	9, 5	1.19 (0.85, 1.66)	1.96 (1.39, 2.76)	4.71 (2.66, 8.33) n=9, 4
Saquinavir
Hard gel formulation	600 single dose	800 three times daily, 2 days	6	4.7 (2.7, 8.1)	6.0 (4.0, 9.1)	2.9 (1.7, 4.7)C_6hr
Soft gel formulation	800 single dose	800 three times daily, 2 days	6	6.5 (4.7, 9.1)	7.2 (4.3, 11.9)	5.5 (2.2, 14.1)
Soft gel formulation	1200 single dose	800 three times daily, 2 days	6	4.0 (2.7, 5.9)	4.6 (3.2, 6.7)	5.5 (3.7, 8.3)
Sildenafil	25 single dose	800 three times daily	6	See text below for discussion of interaction.
StavudineStudy conducted in HIV-positive subjects.	40 twice daily, 7 days	800 three times daily, 7 days	13	0.86 (0.73, 1.03)	1.21 (1.09, 1.33)	Not Done
Theophylline	250 single dose (on Days 1 and 7)	800 three times daily, 6 days (Days 2 to 7)	12, 4	0.88 (0.76, 1.03)	1.14 (1.04, 1.24)	1.13 (0.86, 1.49) n=7, 3
Trimethoprim/ Sulfamethoxazole
Trimethoprim	800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days	400 q6h, 7 days	12	1.18 (1.05, 1.32)	1.18 (1.05, 1.33)	1.18 (1.00, 1.39)
Trimethoprim/ Sulfamethoxazole
Sulfamethoxazole	800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days	400 q6h, 7 days	12	1.01 (0.95, 1.08)	1.05 (1.01, 1.09)	1.05 (0.97, 1.14)
Vardenafil	10 single dose	800 three times daily	18	See text below for discussion of interaction.
Zidovudine	200 three times daily, 7 days	1000 three times daily, 7 days	12	0.89 (0.73, 1.09)	1.17 (1.07, 1.29)	1.51 (0.71, 3.20) n=4
Zidovudine/ Lamivudine
Zidovudine	200/150 three times daily, 7 days	800 three times daily, 7 days	6, 7	1.23 (0.74, 2.03)	1.39 (1.02, 1.89)	1.08 (0.77, 1.50) n=5, 5
Zidovudine/ Lamivudine
Lamivudine	200/150 three times daily, 7 days	800 three times daily, 7 days	6, 7	0.73 (0.52, 1.02)	0.91 (0.66, 1.26)	0.88 (0.59, 1.33)

Table name:

Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name:

Table II. Clinically significant drug interactions with theophylline*.
Drug		Type of Interaction	Effect**
*Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
**Average effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine		Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.
Alcohol		A single large dose of alcohol (3 ml/kg of whiskey) decreases theophylline clearance for up to 24 hours.	30% increase
Allopurinol		Decreases theophylline clearance at doses >600 mg/day.	25% increase at allopurinol
Amino glutethimide		Increases theophylline clearance by induction of microsomal enzyme activity.	25% decrease
Carbamazepine		Similar to aminoglutethimide.	30% decrease
Cimetidine		Decreases theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase
Ciprofloxacin		Similar to cimetidine.	40% increase
Clarithromycin		Similar to erythromycin.	25% increase
Diazepam		Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.	Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram		Decreases theophylline clearance by inhibiting hydroxylation and demethylation.	50% increase
Enoxacin		Similar to cimetidine.	300% increase
Ephedrine		Synergistic CNS effects	Increased frequency of nausea, nervousness, and insomnia.
Erythromycin		Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen		Estrogen containing oral contraceptives decrease theophylline clearance in a dose- dependent fashion. The effect of progesterone on theophylline clearance is unknown.	30% increase
Flurazepam		Similar to diazepam.	Similar to diazepam.
Fluvoxamine		Similar to cimetidine	Similar to cimetidine
Halothane		Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.	Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A		Decreases theophylline clearance.	100% increase
Isoproterenol (IV)	Increases theophylline clearance.		20% decrease
Ketamine	Pharmacologic		May lower theophylline seizure threshold.
Lithium	Theophylline increases renal lithium clearance.		Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam	Similar to diazepam.		Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.		20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine	Similar to disulfiram.		80% increase
Midazolam	Similar to diazepam.		Similar to diazepam.
Moricizine	Increases theophylline clearance.		25% decrease
Pancuronium	Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.		Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline	Decreases theophylline clearance.		30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.		25% decrease after two weeks of concurrent PB.
Phenytoin	Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.		Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone	Decreases theophylline clearance and pharmacologic interaction.		40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and pharmacologic interaction.		100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin	Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.		20-40% decrease
Sulfinpyrazone	Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.		20% decrease
Tacrine	Similar to cimetidine, also increases renal clearance of theophylline.		90% increase
Thiabendazole	Decreases theophylline clearance.		190% increase
Ticlopidine	Decreases theophylline clearance.		60% increase
Troleandomycin	Similar to erythromycin.		33-100% increase depending on troleandomycin dose.
Verapamil	Similar to disulfiram.		20% increase

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.12, 7.3)

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine, danazol	Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem	Do not exceed 40 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Drugs That Interfere with Hemostasis
Clinical Impact	Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention	Monitor patients with concomitant use of diclofenac sodium topical solution with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)]
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of NSAID alone [see Warnings and Precautions (5.2)]
Intervention	Concomitant use of diclofenac sodium topical solution and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Diclofenac sodium topical solution is not a substitute for low dose aspirin for cardiovascular protection.
ACE inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of diclofenac sodium topical solution and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of diclofenac sodium topical solution and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)] When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDS reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of diclofenac sodium topical solution with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact:	The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life digoxin.
Intervention:	During concomitant use of diclofenac sodium topical solution and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDS have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of diclofenac sodium topical solution and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact;	Concomitant use of NSAIDs and methotrexate may increase the risk of methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of diclofenac sodium topical solution and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of diclofenac sodium topical solution and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of diclofenac sodium topical solution and cyclosporine, monitor patients for signs or worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Concomitant use of oral NSAIDs with diclofenac sodium topical solution has been evaluated in one Phase 3 controlled trial and in combination with oral diclofenac, compared to oral diclofenac alone, resulted in a higher rate of rectal hemorrhage (3% vs. less than 1%), and more frequent abnormal creatinine (12% vs. 7%), urea (20% vs. 12%) and hemoglobin (13% vs. 9%).
Intervention:	The concomitant use of diclofenac with other NSAIDs or salicyclates is not recommended. Do not use combination therapy with diclofenac sodium topical solution and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations.
Pemetrexed
Clinical Impact:	Concomitant use of diclofenac sodium topical solution and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of diclofenac sodium topical solution and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives 9 e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistatcontaining products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin dailyFor patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Figure 6: Mean Standing Systolic Blood Pressure Change from Baseline

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline. Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol, systemic and inhaled	lomefloxacin mebendazole
amoxicillin	medroxyprogesterone
ampicillin, with or without sulbactam	methylprednisolone metronidazole
atenolol	metoprolol
azithromycin	nadolol
caffeine, dietary ingestion	nifedipine nizatidine
cefactor	norfloxacin
co-trimoxazole (trimethoprim and sulfamethoxazole)	ofloxacin omeprazole prednisone, prednisolone
diltiazem	ranitidine
dirithromycin	rifabutin
enflurane	roxithromycin
famotidine	sorbitol
felodipine finasteride hydrocortisone	(purgative doses do not inhibit theophylline absorption)
isoflurane	sucralfate
isoniazid	terbutaline, systemic
isradipine	terfenadine
influenza vaccine	tetracycline
ketoconazole	tocainide

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion–the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide(including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T ₄ and T ₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide(including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT ₄. Continued administration results in a decrease in serum T ₄, and normal FT ₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T ₄ and T ₃ to TBG and transthyretin. An initial increase in serum FT ₄ is followed by return of FT ₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T ₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T ₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5’-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T ₄ to T ₃, leading to decreased T ₃ levels. However, serum T ₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T ₃ and T ₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T ₃ concentrations by 30% with minimal change in serum T ₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T ₃ and T ₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄ . Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³ I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 3Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Table 1: Clinically Significant Drug Interactions with Morphine Sulfate Oral Solution
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.5)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Morphine Sulfate Oral Solution if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.3, 5.7)].
Intervention:	Do not use Morphine Sulfate Oral Solution in patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of Morphine Sulfate Oral Solution and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine,
Muscle Relaxants
Clinical Impact:	Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Morphine Sulfate Oral Solution and/or the muscle relaxant as necessary.
Cimetidine
Clinical Impact:	The concomitant use of morphine and cimetidine has been reported to precipitate apnea, confusion, and muscle twitching in an isolated report.
Intervention:	Monitor patients for increased respiratory and CNS depression when Morphine Sulfate Oral Solution is used concomitantly with cimetidine.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when Morphine Sulfate Oral Solution is used concomitantly with anticholinergic drugs.
P-Glycoprotein (P-gp) Inhibitors
Clinical Impact:	The concomitant use of P-gp inhibitors can increase the exposure to morphine by two-fold and can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Morphine Sulfate Oral Solution and/or the P-gp inhibitor as necessary.
Examples:	quinidine, verapamil

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily*
Grapefruit juice	Avoid grapefruit juice

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.12, 7.3)

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Table 7: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [See Clinical Pharmacology (12.3) for Magnitude of Interaction, Tables 10 and 11]
Concomitant Drug Class: Drug Name	Effect on Concentration of Darunavir or Concomitant Drug	Clinical Comment
HIV-Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
didanosine	↔ darunavir ↔ didanosine	Didanosine should be administered one hour before or two hours after PREZISTA/ritonavir (which are administered with food).
HIV-Antiviral Agents: HIV-Protease Inhibitors (PIs)
indinavir (The reference regimen for indinavir was indinavir/ritonavir 800/100 mg twice daily.)	↑ darunavir ↑ indinavir	The appropriate dose of indinavir in combination with PREZISTA/ritonavir has not been established.
lopinavir/ritonavir	↓ darunavir ↔ lopinavir	Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer lopinavir/ritonavir and PREZISTA, with or without ritonavir.
saquinavir	↓ darunavir ↔ saquinavir	Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer saquinavir and PREZISTA, with or without ritonavir.
HIV-Antiviral Agents: CCR5 co-receptor antagonists
Maraviroc	↑ maraviroc	Maraviroc concentrations are increased when co-administered with PREZISTA/rtv. When used in combination with PREZISTA/rtv, the dose of maraviroc should be 150 mg twice daily.
Other Agents
Antiarrhythmics: bepridil, lidocaine (systemic), quinidine, amiodarone, flecainide, propafenone	↑ antiarrhythmics	Concentrations of these drugs may be increased when co-administered with PREZISTA/ritonavir. Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when co-administered with PREZISTA/ritonavir.
digoxin	↑ digoxin	The lowest dose of digoxin should initially be prescribed. The serum digoxin concentrations should be monitored and used for titration of digoxin dose to obtain the desired clinical effect.
Anticoagulant: warfarin	↓ warfarin ↔ darunavir	Warfarin concentrations are decreased when co-administered with PREZISTA/ritonavir. It is recommended that the international normalized ratio (INR) be monitored when warfarin is combined with PREZISTA/ritonavir.
Anticonvulsant: carbamazepine	↔ darunavir ↑ carbamazepine	The dose of either darunavir/ritonavir or carbamazepine does not need to be adjusted when initiating co-administration with darunavir/ritonavir and carbamazepine. Clinical monitoring of carbamazepine concentrations and its dose titration is recommended to achieve the desired clinical response.
Anticonvulsant: phenobarbital, phenytoin	↔ darunavir ↓ phenytoin ↓ phenobarbital	Co-administration of PREZISTA/ritonavir may cause decrease in the steady-state concentrations of phenytoin and phenobarbital. Phenytoin and phenobarbital levels should be monitored when co-administering with PREZISTA/ritonavir.
Antidepressant: trazodone, desipramine	↑ trazodone ↑ desipramine	Concomitant use of trazodone or desipramine and PREZISTA/ritonavir may increase plasma concentrations of trazodone or desipramine which may lead to adverse events such as nausea, dizziness, hypotension and syncope. If trazodone or desipramine is used with PREZISTA/ritonavir, the combination should be used with caution and a lower dose of trazodone or desipramine should be considered.
Anti-infective: clarithromycin	↔ darunavir ↑ clarithromycin	No dose adjustment of the combination is required for patients with normal renal function. For patients with renal impairment, the following dose adjustments should be considered: For subjects with CLcr of 30-60 mL/min, the dose of clarithromycin should be reduced by 50%. For subjects with CLcr of < 30 mL/min, the dose of clarithromycin should be reduced by 75%.
Antifungals: ketoconazole, itraconazole, voriconazole	↑ ketoconazole ↑ darunavir ↑ itraconazole (not studied) ↓ voriconazole (not studied)	Ketoconazole and itraconazole are potent inhibitors as well as substrates of CYP3A. Concomitant systemic use of ketoconazole, itraconazole, and darunavir/ritonavir may increase plasma concentration of darunavir.
		Plasma concentrations of ketoconazole or itraconazole may be increased in the presence of darunavir/ritonavir. When co-administration is required, the daily dose of ketoconazole or itraconazole should not exceed 200 mg.
		Plasma concentrations of voriconazole may be decreased in the presence of darunavir/ritonavir. Voriconazole should not be administered to patients receiving darunavir/ritonavir unless an assessment of the benefit/risk ratio justifies the use of voriconazole.
Anti-gout: colchicine	↑ colchicine	Treatment of gout-flares – co-administration of colchicine in patients on PREZISTA/ritonavir: 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days. Prophylaxis of gout-flares – co-administration of colchicine in patients on PREZISTA/ritonavir: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever – co-administration of colchicine in patients on PREZISTA/ritonavir: maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Patients with renal or hepatic impairment should not be given colchicine with PREZISTA/ritonavir.
Antimycobacterial: rifabutin	↑ darunavir ↑ rifabutin ↑ 25-O-desacetylrifabutin	Dose reduction of rifabutin by at least 75% of the usual dose (300 mg once daily) is recommended (i.e., a maximum dose of 150 mg every other day). Increased monitoring for adverse events is warranted in patients receiving this combination and further dose reduction of rifabutin may be necessary.
The reference regimen for rifabutin was 300 mg once daily	↑ darunavir ↑ rifabutin ↑ 25-O-desacetylrifabutin
β-Blockers: metoprolol, timolol	↑ beta-blockers	Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir.
Benzodiazepines: parenterally administered midazolam	↑ midazolam	Concomitant use of parenteral midazolam with PREZISTA/ritonavir may increase plasma concentrations of midazolam. Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Co-administration of oral midazolam with PREZISTA/ritonavir is CONTRAINDICATED.
Calcium Channel Blockers: felodipine, nifedipine, nicardipine	↑ calcium channel blockers	Plasma concentrations of calcium channel blockers (e.g., felodipine, nifedipine, nicardipine) may increase when PREZISTA/ritonavir are co-administered. Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid: Systemic: dexamethasone	↓ darunavir	Systemic dexamethasone induces CYP3A and can thereby decrease darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA.
Corticosteroid: Inhaled/Nasal: fluticasone	↑ fluticasone	Concomitant use of inhaled fluticasone and PREZISTA/ritonavir may increase plasma concentrations of fluticasone. Alternatives should be considered, particularly for long term use.
Endothelin receptor antagonists: bosentan	↑ bosentan	Co-administration of bosentan in patients on PREZISTA/ritonavir: In patients who have been receiving PREZISTA/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Co-administration of PREZISTA/ritonavir in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of PREZISTA/ritonavir. After at least 10 days following the initiation of PREZISTA/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitors: pravastatin, atorvastatin, rosuvastatin	↑ pravastatin ↑ atorvastatin ↑ rosuvastatin	Use the lowest possible dose of atorvastatin, pravastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as fluvastatin in combination with PREZISTA/ritonavir.
Immunosuppressants: cyclosporine, tacrolimus, sirolimus	↑ immunosuppressants	Plasma concentrations of cyclosporine, tacrolimus or sirolimus may be increased when co-administered with PREZISTA/ritonavir. Therapeutic concentration monitoring of the immunosuppressive agent is recommended when co-administered with PREZISTA/ritonavir.
Inhaled beta agonist: salmeterol	↑ salmeterol	Concurrent administration of salmeterol and PREZISTA/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic/Treatment of Opioid Dependence: methadone, buprenorphine, buprenorphine/naloxone	↓ methadone ↔ buprenorphine, naloxone ↑ norbuprenorphine (metabolite)	No adjustment of methadone dosage is required when initiating co-administration of PREZISTA/ritonavir. However, clinical monitoring is recommended as the dose of methadone during maintenance therapy may need to be adjusted in some patients. No dose adjustment for buprenorphine or buprenorphine/naloxone is required with concurrent administration of PREZISTA/ritonavir. Clinical monitoring is recommended if PREZISTA/ritonavir and buprenorphine or buprenorphine/naloxone are coadministered.
Neuroleptics: risperidone, thioridazine	↑ neuroleptics	A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir.
Oral Contraceptives/estrogen: ethinyl estradiol, norethindrone	↓ ethinyl estradiol ↓ norethindrone	Plasma concentrations of ethinyl estradiol are decreased due to induction of its metabolism by ritonavir. Alternative methods of nonhormonal contraception are recommended.
PDE-5 inhibitors: sildenafil, vardenafil, tadalafil	↑ PDE-5 inhibitors (only the use of sildenafil at doses used for treatment of erectile dysfunction has been studied with PREZISTA/ritonavir)	Co-administration with PREZISTA/ritonavir may result in an increase in PDE-5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances and priapism. Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Use of sildenafil is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications (4) ]. The following dose adjustments are recommended for use of tadalafil with PREZISTA/ritonavir: Co-administration of tadalafil in patients on PREZISTA/ritonavir: In patients receiving PREZISTA/ritonavir for at least one week, start tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Co-administration of PREZISTA/ritonavir in patients on tadalafil: Avoid use of tadalafil during the initiation of PREZISTA/ritonavir. Stop tadalafil at least 24 hours prior to starting PREZISTA/ritonavir. After at least one week following the initiation of PREZISTA/ritonavir, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE-5 inhibitors for erectile dysfunction: Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg dose in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours can be used with increased monitoring for PDE-5 inhibitor-associated adverse events.
Selective Serotonin Reuptake Inhibitors (SSRIs): sertraline, paroxetine	↔ darunavir ↓ sertraline ↓ paroxetine	If sertraline or paroxetine is co-administered with PREZISTA/ritonavir, the recommended approach is a careful dose titration of the SSRI based on a clinical assessment of antidepressant response. In addition, patients on a stable dose of sertraline or paroxetine who start treatment with PREZISTA/ritonavir should be monitored for antidepressant response.

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Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
* Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing.
	20 mg/day	4 mg/day	1.6	-	Do not exceed 8 mg/day
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed

Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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AED Coadministered	AED Concentration	Topiramate Concentration
^a= Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. ^b= Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. NE = Not Evaluated
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin	Monitor phenytoin level (7)
Methotrexate	Monitor for methotrexate toxicity (7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)

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Increased Risk of Myopathy/Rhabdomyolysis (2, 5.1, 7, 12.3)
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
Lopinavir plus ritonavir	Use lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 3. Selected Drugs that altered or are predicted to alter the plasma concentration of itraconazole or have their plasma concentration altered by ONMELThis list is not all-inclusive.
Drug plasma concentration increased by itraconazole
Antiarrhythmics	digoxin, dofetilide, quinidine, disopyramide
Anticonvulsants	carbamazepine
Anti-HIV Agents	indinavir, ritonavir, saquinavir, maraviroc
Antineoplastics	busulfan, docetaxel, vinca alkaloids
Antipsychotics	pimozide
Benzodiazepines	alprazolam, diazepam, midazolam,For information on parenterally administered midazolam, see the Benzodiazepine paragraph below. triazolam
Calcium Channel Blockers	dihydropyridines (including nisoldipine and felodipine), verapamil
Gastrointestinal Motility Agents	cisapride
HMG CoA-Reductase Inhibitors	atorvastatin, cerivastatin, lovastatin, simvastatin
Immunosuppressants	Cyclosporine, tacrolimus, sirolimus
Oral Hypoglycemics	oral hypoglycemics (repaglinide)
Opiate Analgesics	fentanyl, levacetylmethadol (levomethadyl), methadone
Polyene Antifungals	amphotericin B
Other	ergot alkaloids, halofantrine, alfentanil, buspirone, methylprednisolone, budesonide, dexamethasone, fluticasone, warfarin, cilostazol, eletriptan, fexofenadine, loperamide

Decrease plasma concentration of itraconazole
Anticonvulsants	carbamazepine, phenobarbital, phenytoin
Anti-HIV Agents	nevirapine, efavirenz
Antimycobacterials	isoniazid, rifabutin, rifampin
Gastric Acid Suppressors/Neutralizers	antacids, H₂-receptor antagonists, proton pump inhibitors

Increase plasma concentration of itraconazole
Macrolide Antibiotics	clarithromycin, erythromycin
Anti-HIV Agents	indinavir, ritonavir

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Table 2: Coagulation Tests Affected and Unaffected by ORBACTIV
Elevated by ORBACTIV	Unaffected by ORBACTIV
Prothrombin time (PT) up to 12 hours	Chromogenic Factor Xa Assay
International normalized ratio (INR) up to 12 hours	Thrombin Time (TT)
Activated partial thromboplastin time (aPTT) up to 120 hours
Activated clotting time (ACT) up to 24 hours
Silica clot time (SCT) up to 18 hours
Dilute Russell’s viper venom time (DRVVT) up to 72 hours
D-dimer up to 72 hours

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Table 2. Selected Drugs That Have Been Shown To or Are Predicted To Alter The Plasma Concentration Of Ketoconazole
*This list is not all-inclusive.
Systemic exposure to ketoconazole is reduced significantly by these drugs: Concomitant use with ketoconazole is not recommended.
Carbamazepine	Phenytoin
Gastric Acid Suppressants (antacids, antimuscarinics, histamine H₂-blockers, proton pump inhibitors, sucralfate)	Rifampin, rifabutin, isoniazid
Nevirapine

Systemic exposure to ketoconazole is increased significantly by this drug: Dose reduction of ketoconazole should be considered
Ritonavir

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T ₄ and T ₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT ₄. Continued administration results in a decrease in serum T ₄ and normal FT ₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T ₄ and T ₃ to TBG and transthyretin. An initial increase in serum FT ₄, is followed by return of FT ₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T ₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T ₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T ₄ to T ₃, leading to decreased T ₃ levels. However, serum T ₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T ₃ and T ₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T ₃ concentrations by 30% with minimal change in serum T ₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T ₃ and T ₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 3: Clinically Significant Drug Interactions with HYSINGLA ER
Inhibitors of CYP3A4
Clinical Impact:	The concomitant use of HYSINGLA ER and CYP3A4 inhibitors can increase the plasma concentration of hydrocodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of HYSINGLA ER and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of HYSINGLA ER is achieved [see Warnings and Precautions (5.4)]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the hydrocodone plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to hydrocodone.
Intervention:	If concomitant use is necessary, consider dosage reduction of HYSINGLA ER until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the HYSINGLA ER dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact:	The concomitant use of HYSINGLA ER and CYP3A4 inducers can decrease the plasma concentration of hydrocodone [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to hydrocodone [see Warnings and Precautions (5.4)]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the hydrocodone plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention:	If concomitant use is necessary, consider increasing the HYSINGLA ER dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider HYSINGLA ER dosage reduction and monitor for signs of respiratory depression.
Examples:	Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.5)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue HYSINGLA ER if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
Intervention:	The use of HYSINGLA ER is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	Phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of HYSINGLA ER and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Hydrocodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of HYSINGLA ER and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when HYSINGLA ER is used concomitantly with anticholinergic drugs.
Strong Laxatives
Clinical Impact:	Concomitant use of HYSINGLA ER with strong laxatives that rapidly increase gastrointestinal motility, may decrease hydrocodone absorption and result in decreased hydrocodone plasma levels.
Intervention:	If HYSINGLA ER is used in these patients, closely monitor for the development of adverse events as well as changing analgesic requirements.
Example:	Lactulose

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Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue hydromorphone hydrochloride extended-release tablets if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.4)].
Intervention:	The use of hydromorphone hydrochloride extended-release tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of hydromorphone hydrochloride extended-release tablets and/or precipitate withdrawal symptoms [see Warnings and Precautions (5.11)].
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Hydromorphone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression [see Warnings and Precautions (5.4)].
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of hydromorphone hydrochloride extended-release tablets and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when hydromorphone hydrochloride extended-release tablets are used concomitantly with anticholinergic drugs.

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Table 3Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Bleeding times
Clinical Impact:	Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention:	This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact:	The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention:	Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact:	Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention:	This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.

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Table 2: Clinically Significant Drug Interactions with Oxymorphone Hydrochloride Tablets
Alcohol
Clinical Impact:	The concomitant use of alcohol with oxymorphone hydrochloride tablets can result in an increase of oxymorphone plasma levels and potentially fatal overdose of oxymorphone.
Intervention:	Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while on oxymorphone hydrochloride tablets therapy [see Clinical Pharmacology (12.3)].
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines and other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue oxymorphone hydrochloride tablets if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)]. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Intervention:	The use of oxymorphone hydrochloride tablets are not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of oxymorphone hydrochloride tablets and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Oxymorphone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of oxymorphone hydrochloride tablets and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when oxymorphone hydrochloride tablets are used concomitantly with anticholinergic drugs.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when oxymorphone hydrochloride tablets are used concomitantly with anticholinergic drugs.
Cimetidine
Clinical Impact:	Cimetidine can potentiate opioid-induced respiratory depression.
Intervention:	Monitor patients for respiratory depression when oxymorphone hydrochloride tablets and cimetidine are used concurrently.

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Table 4. Drugs That May Alter Hepatic Metabolism of T4 (Hypothyroidism)
Potential impact: Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased SYNTHROID requirements.
Drug or Drug Class	Effect
Phenobarbital Rifampin	Phenobarbital has been shown to reduce the response to thyroxine. Phenobarbital increases L-thyroxine metabolism by inducing uridine 5’-diphospho-glucuronosyltransferase (UGT) and leads to a lower T4 serum levels. Changes in thyroid status may occur if barbiturates are added or withdrawn from patients being treated for hypothyroidism. Rifampin has been shown to accelerate the metabolism of levothyroxine.

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Interacting Drug	Interaction
Multivalent cation-containing products including: antacids, sucralfate, multivitamins	Decreased moxifloxacin hydrochloride absorption. Take moxifloxacin hydrochloride tablet at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time/INR, and bleeding. (6, 7.2, 12.3)
Class IA and Class III antiarrhythmics:	Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.6, 7.5)
Antidiabetic agents	Carefully monitor blood glucose. (5.11, 7.3)

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Table 7: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (C_max and AUC_τ after 200 mg q12h)	Recommendations for Voriconazole Dosage Adjustment/Comments
RifampinResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects and Rifabutin (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (400 mg q24h)Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (300 mg q24h) (CYP450 Induction)	Slight Decrease in AUC _τ	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h) (CYP450 Induction)	Significantly Reduced	Contraindicated
Low-dose Ritonavir (100 mg q12h) (CYP450 Induction)	Reduced	Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Phenytoin (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John's Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir

	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to voriconazole

	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Careful assessment of voriconazole effectiveness

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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Interacting Drug	Interaction
Valproic acid	Doripenem reduced the serum concentrations of valproic acid to below the therapeutic concentration range in healthy subjects (7.1)
Probenecid	Reduces renal clearance of doripenem, resulting in increased doripenem concentrations (7.2, 12.3)
Drugs metabolized by cytochrome P450 enzymes	Doripenem neither inhibits nor induces major cytochrome P450 enzymes (12.3)

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Table 1 Changes in Desloratadine and 3-Hydroxydesloratadine Pharmacokinetics in Healthy Male and Female Volunteers
	Desloratadine		3-Hydroxydesloratadine
	C_max	AUC 0–24 hrs	C_max	AUC 0–24 hrs
Erythromycin (500 mg Q8h)	+24%	+14%	+43%	+40%
Ketoconazole (200 mg Q12h)	+45%	+39%	+43%	+72%
Azithromycin (500 mg day 1, 250 mg QD × 4 days)	+15%	+5%	+15%	+4%
Fluoxetine (20 mg QD)	+15%	+0%	+17%	+13%
Cimetidine (600 mg Q12h)	+12%	+19%	-11%	-3%

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
↓= Decreased (induces lamotrigine gluronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ?= Conflicting data.
Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine (CBZ) and CBZ epoxide	? CBZ epoxide	May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Factors	Dosage Adjustments for Aripiprazole
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors	Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double usual dose over 1 to 2 weeks

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Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir )	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)	Do not exceed 40 mg atorvastatin daily

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Table 1: Clinically Significant Drug Interactions with Morphine Sulfate Extended-Release Capsules

Alcohol
Clinical Impact:	Concomitant use of alcohol with Morphine Sulfate Extended-Release Capsules can result in an increase of morphine plasma levels and potentially fatal overdose of morphine.
Intervention:	Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while on Morphine Sulfate Extended-Release Capsules therapy [see Clinical Pharmacology (12.3)].
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepine or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers and muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Morphine Sulfate Extended-Release Capsules if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT₃ receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
Intervention:	Do not use Morphine Sulfate Extended-Release Capsules in patients taking MAOIs or within 14 days of stopping such treatment.
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of Morphine Sulfate Extended-Release Capsules and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Morphine Sulfate Extended-Release Capsules and/or the muscle relaxant as necessary.
Cimetidine
Clinical Impact:	The concomitant use of cimetidine can potentiate morphine effects and increase risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Morphine Sulfate Extended-Release Capsules and/or cimetidine as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when Morphine Sulfate Extended-Release Capsules are used concomitantly with anticholinergic drugs.
P-Glycoprotein (PGP) Inhibitors
Clinical Impact:	The concomitant use of PGP-inhibitors can increase the exposure to morphine by about two-fold and can increase risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Morphine Sulfate Extended-Release Capsules and/or the PGP-inhibitor as necessary.

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Bleeding times
Clinical Impact:	Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention:	This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact:	The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention:	Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact:	Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention:	This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
	? CBZ epoxide	May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistatcontaining products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin dailyFor patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Table 4: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [see Clinical Pharmacology (12.3)]
Concomitant Drug Class: Drug Name	Effect on Concentration of Rilpivirine or Concomitant Drug	Clinical Comment
↑ = increase, ↓ = decrease, ↔ = no change
HIV-Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
didanosineThe interaction between EDURANT and the drug was evaluated in a clinical study. All other drug-drug interactions shown are predicted. This interaction study has been performed with a dose higher than the recommended dose for EDURANT assessing the maximal effect on the co-administered drug. The dosing recommendation is applicable to the recommended dose of EDURANT 25 mg once daily.	↔ rilpivirine ↔ didanosine	No dose adjustment is required when EDURANT is co-administered with didanosine. Didanosine is to be administered on an empty stomach and at least two hours before or at least four hours after EDURANT (which should be administered with a meal).
HIV-Antiviral Agents: Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
NNRTI (delavirdine)	↑ rilpivirine ↔ delavirdine	It is not recommended to co-administer EDURANT with delavirdine and other NNRTIs.
Other NNRTIs (efavirenz, etravirine, nevirapine)	↓ rilpivirine ↔ other NNRTIs
HIV-Antiviral Agents: Protease Inhibitors (PIs)-Boosted (i.e., with co-administration of low-dose ritonavir) or Unboosted (i.e., without co-administration of low-dose ritonavir)
darunavir/ritonavir	↑ rilpivirine ↔ boosted darunavir	Concomitant use of EDURANT with darunavir/ritonavir may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when EDURANT is co-administered with darunavir/ritonavir.
lopinavir/ritonavir	↑ rilpivirine ↔ boosted lopinavir	Concomitant use of EDURANT with lopinavir/ritonavir may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when EDURANT is co-administered with lopinavir/ritonavir.
other boosted PIs (atazanavir/ritonavir, fosamprenavir/ritonavir, saquinavir/ritonavir, tipranavir/ritonavir)	↑ rilpivirine ↔ boosted PI	Concomitant use of EDURANT with boosted PIs may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). EDURANT is not expected to affect the plasma concentrations of co-administered PIs.
unboosted PIs (atazanavir, fosamprenavir, indinavir, nelfinavir)	↑ rilpivirine ↔ unboosted PI	Concomitant use of EDURANT with unboosted PIs may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). EDURANT is not expected to affect the plasma concentrations of co-administered PIs.
Other Agents
Antacids: antacids (e.g., aluminum or magnesium hydroxide, calcium carbonate)	↔ rilpivirine (antacids taken at least 2 hours before or at least 4 hours after rilpivirine)	The combination of EDURANT and antacids should be used with caution as co-administration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). Antacids should only be administered either at least 2 hours before or at least 4 hours after EDURANT.
	↓ rilpivirine (concomitant intake)
Antimycobacterials: rifabutin	↓ rilpivirine	Concomitant use of EDURANT with rifabutin may cause a decrease in the plasma concentrations of rilpivirine (induction of CYP3A enzymes). Throughout co-administration of EDURANT with rifabutin, the EDURANT dose should be increased from 25 mg once daily to 50 mg once daily. When rifabutin co-administration is stopped, the EDURANT dose should be decreased to 25 mg once daily.
Azole Antifungal Agents: fluconazole itraconazole ketoconazole posaconazole voriconazole	↑ rilpivirine ↓ ketoconazole	Concomitant use of EDURANT with azole antifungal agents may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No rilpivirine dose adjustment is required when EDURANT is co-administered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are co-administered with EDURANT.
H₂-Receptor Antagonists: cimetidine famotidine nizatidine ranitidine	↔ rilpivirine (famotidine taken 12 hours before rilpivirine or 4 hours after rilpivirine)	The combination of EDURANT and H₂-receptor antagonists should be used with caution as co-administration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). H₂-receptor antagonists should only be administered at least 12 hours before or at least 4 hours after EDURANT.
	↓ rilpivirine (famotidine taken 2 hours before rilpivirine)
Macrolide or ketolide antibiotics: clarithromycin erythromycin telithromycin	↑ rilpivirine ↔ clarithromycin ↔ erythromycin ↔ telithromycin	Concomitant use of EDURANT with clarithromycin, erythromycin or telithromycin may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Where possible, alternatives such as azithromycin should be considered.
Narcotic Analgesics: methadone	↓ R(-) methadone ↓ S(+) methadone	No dose adjustments are required when initiating co-administration of methadone with EDURANT. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients.

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Table 4: Clinically Relevant Interactions Affecting Omeprazole When Co-Administered with Other Drugs
CYP2C19 or CYP3A4 Inducers
Clinical Impact:	Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention:	St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions (5.9)]. Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:	Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
Intervention:	Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 18. Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9- Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Co-administered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference)		Risperidone Dose Recommendation
	Co-administered Drug	Risperidone	AUC	C_max
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Drug Name	Effect on Concentration of Nevirapine or Concomitant Drug	Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/ Ritonavir*	¯ Atazanavir Nevirapine	Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir*	¯Amprenavir Nevirapine	Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/ Ritonavir*	¯Amprenavir Nevirapine	No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir*	¯ Indinavir	The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/ Ritonavir*	¯Lopinavir	Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
		Dosing in pediatric patients: Please refer to the Kaletra^® prescribing information for dosing recommendations based on body surface area and body weight.Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir*	¯Nelfinavir M8 Metabolite ¯Nelfinavir C_min	The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/ Ritonavir	The interaction between nevirapine saquinavir/ritonavir has not been evaluated	The appropriate doses of the combination of and nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
Drug Name	Effect on Concentration of Nevirapine or Concomitant Drug	Clinical Comment
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz*	¯ Efavirenz	The appropriate doses of these combinations with respect to safety and efficacy have not been established.
Delavirdine Etravirine Rilpivirine		Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.
Hepatitis C Antiviral Agents
Boceprevir	Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine	Nevirapine and boceprevir should not be coadministered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy.
Telaprevir	Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir.	Nevirapine and telaprevir should not be coadministered because changes in plasma concentrations of nevirapine, telaprevir, or both may be may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events.
Other Agents
Analgesics: Methadone*	¯ Methadone	Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics: Amiodarone, disopyramide, lidocaine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Antibiotics: Clarithromycin*	¯ Clarithromycin 14-OH clarithromyci	Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium aviumintracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Rifabutin*	Rifabutin	Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Drug Name	Effect on Concentration of Nevirapine or Concomitant Drug	Clinical Comment
Rifampin*	¯ Nevirapine	Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants: Carbamazepine, clonazepam, ethosuximide	Plasma concentrations of nevirapine and the anticonvulsant may be decreased.	Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals: Fluconazole*	Nevirapine	Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Ketoconazole*	¯ Ketoconazole	Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Itraconazole	¯ Itraconazole	Nevirapine and itraconazole should not be administered concomitantly due to potentia decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics: Warfarin	Plasma concentrations may be increased.	Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers: Diltiazem, nifedipine, verapamil	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Cancer chemotherapy: Cyclophosphamide	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Ergot alkaloids: Ergotamine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Motility agents: Cisapride	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Opiate agonists: Fentanyl	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Oral contraceptives: Ethinyl estradiol and Norethindrone*	¯Ethinyl estradiol ¯ Norethindrone	Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.
* The interaction between nevirapine and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.

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CYP2C19 or CYP3A4 Inducers
Clinical Impact:	Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention:	St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions (5.9)]. Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:	Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
Intervention:	Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole.

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Summary of AED interactions with topiramate ( 7.1).
AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase ^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide ^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400mg/day	13% decrease

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Bleeding times
Clinical Impact:	Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention:	This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact:	The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention:	Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact:	Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention:	This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.

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Table II. Clinically significant drug interactions with theophylline*.
Drug		Type of Interaction	Effect**
*Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
**Average effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine		Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.
Alcohol		A single large dose of alcohol (3 ml/kg of whiskey) decreases theophylline clearance for up to 24 hours.	30% increase
Allopurinol		Decreases theophylline clearance at allopurinol doses >600 mg/day.	25% increase
Aminoglutethimide		Increases theophylline clearance by induction of microsomal enzyme activity.	25% decrease
Carbamazepine		Similar to aminoglutethimide.	30% decrease
Cimetidine		Decreases theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase
Ciprofloxacin		Similar to cimetidine.	40% increase
Clarithromycin		Similar to erythromycin.	25% increase
Diazepam		Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.	Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram		Decreases theophylline clearance by inhibiting hydroxylation and demethylation.	50% increase
Enoxacin		Similar to cimetidine.	300% increase
Ephedrine		Synergistic CNS effects	Increased frequency of nausea, nervousness, and insomnia.
Erythromycin		Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen		Estrogen containing oral contraceptives decrease theophylline clearance in a dose- dependent fashion. The effect of progesterone on theophylline clearance is unknown.	30% increase
Flurazepam		Similar to diazepam.	Similar to diazepam.
Fluvoxamine		Similar to cimetidine	Similar to cimetidine
Halothane		Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.	Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A		Decreases theophylline clearance.	100% increase
Isoproterenol (IV)	Increases theophylline clearance.		20% decrease
Ketamine	Pharmacologic		May lower theophylline seizure threshold.
Lithium	Theophylline increases renal lithium clearance.		Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam	Similar to diazepam.		Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.		20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine	Similar to disulfiram.		80% increase
Midazolam	Similar to diazepam.		Similar to diazepam.
Moricizine	Increases theophylline clearance.		25% decrease
Pancuronium	Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.		Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline	Decreases theophylline clearance.		30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.		25% decrease after two weeks of concurrent PB.
Phenytoin	Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.		Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone	Decreases theophylline clearance and pharmacologic interaction.		40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and pharmacologic interaction.		100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin	Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.		20-40% decrease
Sulfinpyrazone	Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.		20% decrease
Tacrine	Similar to cimetidine, also increases renal clearance of theophylline.		90% increase
Thiabendazole	Decreases theophylline clearance.		190% increase
Ticlopidine	Decreases theophylline clearance.		60% increase
Troleandomycin	Similar to erythromycin.		33-100% increase depending on troleandomycin dose.
Verapamil	Similar to disulfiram.		20% increase

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Figure 5: Mean Standing Systolic Blood Pressure Change from Baseline

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Digoxin concentrations increased greater than 50%
	Digoxin Serum Concentration Increase	Digoxin AUC Increase	Recommendations
Amiodarone	70%	NA	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30% to 50% or by modifying the dosing frequency and continue monitoring.
Captopril	58%	39%
Clarithromycin	NA	70%
Dronedarone	NA	150%
Gentamicin	129% to 212%	NA
Erythromycin	100%	NA
Itraconazole	80%	NA
Lapatinib	NA	180%
Nitrendipine	57%	15%
Propafenone	NA	60% to 270%
Quinidine	100%	NA
Ranolazine	50%	NA
Ritonavir	NA	86%
Telaprevir	50%	85%
Tetracycline	100%	NA
Verapamil	50% to 75%	NA
Digoxin concentrations increased less than 50%
Atorvastatin	22%	15%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15% to 30% or by modifying the dosing frequency and continue monitoring.
Carvedilol	16%	14%
Conivaptan	33%	43%
Diltiazem	20%	NA
Indomethacin	40%	NA
Nefazodone	27%	15%
Nifedipine	45%	NA
Propantheline	24%	24%
Quinine	NA	33%
Rabeprazole	29%	19%
Saquinavir	27%	49%
Spironolactone	25%	NA
Telmisartan	20% to 49%	NA
Ticagrelor	31%	28%
Tolvaptan	30%	NA
Trimethoprim	22% to 28%	NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate and sulfasalazine			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20% to 40% as necessary.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir )	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)	Do not exceed 40 mg atorvastatin daily

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Table II. Clinically significant drug interactions with theophylline*.
Drug		Type of Interaction	Effect**
*Refer to for further information regarding table. PRECAUTIONS, Drug Interactions
**Average effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine		Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.
Alcohol		A single large dose of alcohol (3 ml/kg of whiskey) decreases theophylline clearance for up to 24 hours.	30% increase
Allopurinol		Decreases theophylline clearance at allopurinol doses 600 mg/day. >	25% increase
Amino glutethimide		Increases theophylline clearance by induction of microsomal enzyme activity.	25% decrease
Carbamazepine		Similar to aminoglutethimide.	30% decrease
Cimetidine		Decreases theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase
Ciprofloxacin		Similar to cimetidine.	40% increase
Clarithromycin		Similar to erythromycin.	25% increase
Diazepam		Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.	Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram		Decreases theophylline clearance by inhibiting hydroxylation and demethylation.	50% increase
Enoxacin		Similar to cimetidine.	300% increase
Ephedrine		Synergistic CNS effects	Increased frequency of nausea, nervousness, and insomnia.
Erythromycin		Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen		Estrogen containing oral contraceptives decrease theophylline clearance in a dose- dependent fashion. The effect of progesterone on theophylline clearance is unknown.	30% increase
Flurazepam		Similar to diazepam.	Similar to diazepam.
Fluvoxamine		Similar to cimetidine	Similar to cimetidine
Halothane		Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.	Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A		Decreases theophylline clearance.	100% increase
Isoproterenol (IV)	Increases theophylline clearance.		20% decrease
Ketamine	Pharmacologic		May lower theophylline seizure threshold.
Lithium	Theophylline increases renal lithium clearance.		Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam	Similar to diazepam.		Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.		20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine	Similar to disulfiram.		80% increase
Midazolam	Similar to diazepam.		Similar to diazepam.
Moricizine	Increases theophylline clearance.		25% decrease
Pancuronium	Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.		Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline	Decreases theophylline clearance.		30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.		25% decrease after two weeks of concurrent PB.
Phenytoin	Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.		Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone	Decreases theophylline clearance and pharmacologic interaction.		40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and pharmacologic interaction.		100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin	Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.		20-40% decrease
Sulfinpyrazone	Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.		20% decrease
Tacrine	Similar to cimetidine, also increases renal clearance of theophylline.		90% increase
Thiabendazole	Decreases theophylline clearance.		190% increase
Ticlopidine	Decreases theophylline clearance.		60% increase
Troleandomycin	Similar to erythromycin.		33-100% increase depending on troleandomycin dose.
Verapamil	Similar to disulfiram.		20% increase

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AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxideIs not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs that Interfere with Hemostasis
Clinical Impact :	Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention :	Monitor patients with concomitant use of Meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact :	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention :	Concomitant use of Meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors , Angiotensin Receptor Blockers , or Beta - Blockers
Clinical Impact :	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention :	During concomitant use of Meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of Meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact :	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention :	During concomitant use of Meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Lithium
Clinical Impact :	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology (12.3)].
Intervention :	During concomitant use of Meloxicam and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact :	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention :	During concomitant use of Meloxicam and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact :	Concomitant use of Meloxicam and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention :	During concomitant use of Meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact :	Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention :	The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact :	Concomitant use of Meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention :	During concomitant use of Meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.

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Table II. Clinically significant drug interactions with theophylline.Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
Drug	Type of Interaction	EffectAverage effect on steady-state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine	Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.
Alcohol	A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours.	30% increase
Allopurinol	Decreases theophylline clearance at allopurinol doses ≥600 mg/day.	25% increase
Aminoglutethimide	Increases theophylline clearance by induction of microsomal enzyme activity.	25% decrease
Carbamazepine	Similar to aminoglutethimide.	30% decrease
Cimetidine	Decreases theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase
Ciprofloxacin	Similar to cimetidine.	40% increase
Clarithromycin	Similar to erythromycin.	25% increase
Diazepam	Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.	Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram	Decreases theophylline clearance by inhibiting hydroxylation and demethylation.	50% increase
Enoxacin	Similar to cimetidine.	300% increase
Ephedrine	Synergistic CNS effects	Increased frequency of nausea, nervousness, and insomnia.
Erythromycin	Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen	Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.	30% increase
Flurazepam	Similar to diazepam.	Similar to diazepam.
Fluvoxamine	Similar to cimetidine.	Similar to cimetidine.
Halothane	Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.	Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A	Decreases theophylline clearance.	100% increase
Isoproterenol (IV)	Increase theophylline clearance.	20% increase
Ketamine	Pharmacologic	May lower theophylline seizure threshold.
Lithium	Theophylline increases renal lithium clearance.	Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam	Similar to diazepam.	Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.	20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine	Similar to disulfiram.	80% increase
Midazolam	Similar to diazepam.	Similar to diazepam.
Moricizine	Increases theophylline clearance.	25% decrease
Pancuronium	Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.	Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline	Decreases theophylline clearance.	30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.	25% decrease after two weeks of concurrent PB.
Phenytoin	Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.	Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone	Decreases theophylline clearance and pharmacologic interaction.	40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and pharmacologic interaction.	100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin	Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.	20 to 40% decrease
Sulfinpyrazone	Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.	20% increase
Tacrine	Similar to cimetidine, also increases renal clearance of theophylline.	90% increase
Thiabendazole	Decreases theophylline clearance.	190% increase
Ticlopidine	Decreases theophylline clearance.	60% increase
Troleandomycin	Similar to erythromycin.	33 to 100% increase depending on troleandomycin dose.
Verapamil	Similar to disulfiram.	20% increase

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T ₄ and T ₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT ₄. Continued administration results in a decrease in serum T ₄ and normal FT ₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T ₄ and T ₃ to TBG and transthyretin. An initial increase in serum FT ₄, is followed by return of FT ₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T ₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T ₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T ₄ to T ₃, leading to decreased T ₃ levels. However, serum T ₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T ₃ and T ₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T ₃ concentrations by 30% with minimal change in serum T ₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T ₃ and T ₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

Table name:

Table 3Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

Table name:

AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NCor25%increase^a	48%decrease
Carbamazepine(CBZ)	NC	40%decrease
CBZepoxide^b	NC	NE
Valproic acid	11%decrease	14%decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NCatTPM dosesupto400 mg/day	13%decrease

Table name:

Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
*Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing.
	20 mg/day	4 mg/day	1.6	-	Do not exceed 8 mg/day
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers)
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

Table name:

Classes of Drugs
5-lipoxygenase Inhibitor Adrenergic Stimulants, Central Alcohol Abuse Reduction Preparations Analgesics Anesthetics, Inhalation Antiandrogen Antiarrhythmics† Antibiotics† Aminoglycosides (oral) Cephalosporins, parenteral Macrolides Miscellaneous Penicillins, intravenous, high dose Quinolones (fluoroquinolones) Sulfonamides, long acting Tetracyclines Anticoagulants Anticonvulsants† Antidepressants† Antimalarial Agents Antineoplastics† Antiparasitic/Antimicrobials	Antiplatelet Drugs/Effects Antithyroid Drugs† Beta-Adrenergic Blockers Cholelitholytic Agents Diabetes Agents, Oral Diuretics† Fungal Medications, Intravaginal, Systemic† Gastric Acidity and Peptic Ulcer Agents† Gastrointestinal Prokinetic Agents Ulcerative Colitis Agents Gout Treatment Agents Hemorrheologic Agents Hepatotoxic Drugs Hyperglycemic Agents Hypertensive Emergency Agents Hypnotics† Hypolipidemics† Bile Acid-Binding Resins† Fibric Acid Derivatives HMG-CoA Reductase Inhibitors†	Leukotriene Receptor Antagonist Monoamine Oxidase Inhibitors Narcotics, prolonged Nonsteroidal Anti- Inflammatory Agents Proton Pump Inhibitors Psychostimulants Pyrazolones Salicylates Selective Serotonin Reuptake Inhibitors Steroids, Adrenocortical† Steroids, Anabolic (17-Alkyl Testosterone Derivatives) Thrombolytics Thyroid Drugs Tuberculosis Agents† Uricosuric Agents Vaccines Vitamins†

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Table 4Clinically Relevant Interactions Affecting Omeprazole When Co-Administered with Other Drugs
CYP2C19 or CYP3A4 Inducers
Clinical Impact :	Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention :	St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings And Precautions (5.9)]. Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact :	Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
Intervention :	Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole.

Table name: FactorsDosage Adjustments for AripirazoleAdminister half of usual doseAdminister a quarter of usual doseStrong CYP2D6 or CYP3A4 inhibitorsAdminister half of usual doseStrong CYP2D6 and CYP3A4 inhibitorsAdminister a quarter of usual doseStrong CYP3A4 inducersDouble usual dose over 1 to 2 weeks




Known CYP2D6 Poor Metabolizers
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors

Table name:

Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)].
Examples:	Benzodiazepines and other sedative hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue morphine sulfate extended-release tablets if serotonin syndrome is suspected.
Example:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.6)].
Intervention:	Do not use morphine sulfate extended-release tablets in patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of morphine sulfate extended-release tablets and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of morphine sulfate extended-release tablets and/or the muscle relaxant as necessary.
Cimetidine
Clinical Impact:	The concomitant use of cimetidine can potentiate morphine effects and increase risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of morphine sulfate extended-release tablets and/or cimetidine as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when morphine sulfate extended-release tablets are used concomitantly with anticholinergic drugs.
P-Glycoprotein (P-gp) Inhibitors
Clinical Impact:	The concomitant use of PGP-inhibitors can increase the exposure to morphine by about two-fold and can increase risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of morphine sulfate extended-release tablets and/or the PGP-inhibitor as necessary.
Example:	quinidine

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin	Monitor phenytoin level (7)
Methotrexate	Monitor for methotrexate toxicity (7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)

Table name:

Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine,danazol	Do not exceed 10 mg simvastatindaily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem	Do not exceed 40 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Table 8: Clinically Significant Drug Interactions with BIAXIN
Drugs That Are Affected By BIAXIN
Drug(s) with Pharmacokinetics Affected by BIAXIN	Recommendation	Comments
Antiarrhythmics:
Disopyramide Quinidine Dofetilide Amiodarone Sotalol Procainamide	Not Recommended	Disopyramide, Quinidine: There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs [see Warnings and Precautions (5.3)]. Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine. There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.
Digoxin	Use With Caution	Digoxin: Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are co-administered, inhibition of Pgp by clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range.
Oral Anticoagulants:
Warfarin	Use With Caution	Oral anticoagulants: Spontaneous reports in the postmarketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously [see Warnings and Precautions (5.4)].
Antiepileptics:
Carbamazepine	Use With Caution	Carbamazepine: Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered. Increased serum concentrations of carbamazepine were observed in clinical trials with clarithromycin. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with carbamazepine.
Antifungals:
Itraconazole	Use With Caution	Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly (see also Itraconazole under “Drugs That Affect BIAXIN” in the table below). Clarithromycin may increase the plasma concentrations of itraconazole. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions.
Fluconazole	No Dose Adjustment	Fluconazole: [see Pharmacokinetics (12.3)]
Anti-Gout Agents:
Colchicine (in patients with renal or hepatic impairment)	Contraindicated	Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. The dose of colchicine should be reduced when co-administered with clarithromycin in patients with normal renal and hepatic function [see Contraindications (4.4) and Warnings and Precautions (5.4)].
Colchicine (in patients with normal renal and hepatic function)	Use With Caution
Antipsychotics:
Pimozide	Contraindicated	Pimozide: [See Contraindications (4.2)]
Quetiapine		Quetiapine: Quetiapine is a substrate for CYP3A4, which is inhibited by clarithromycin. Co-administration with clarithromycin could result in increased quetiapine exposure and possible quetiapine related toxicities. There have been postmarketing reports of somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation during concomitant administration. Refer to quetiapine prescribing information for recommendations on dose reduction if co-administered with CYP3A4 inhibitors such as clarithromycin.
Antispasmodics:
Tolterodine (patients deficient in CYP2D6 activity)	Use With Caution	Tolterodine: The primary route of metabolism for tolterodine is via CYP2D6. However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when co-administered with clarithromycin.
Antivirals:
Atazanavir	Use With Caution	Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect BIAXIN” in the table below) [see Pharmacokinetics (12.3)].
Saquinavir (in patients with decreased renal function)		Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction (see Saquinavir under “Drugs That Affect BIAXIN” in the table below) [see Pharmacokinetics (12.3)].
Ritonavir Etravirine		Ritonavir, Etravirine: (see Ritonavir and Etravirine under “Drugs That Affect BIAXIN” in the table below) [see Pharmacokinetics (12.3)].
Maraviroc		Maraviroc: Clarithromycin may result in increases in maraviroc exposures by inhibition of CYP3A metabolism. See Selzentry^® prescribing information for dose recommendation when given with strong CYP3A inhibitors such as clarithromycin.
Boceprevir (in patients with normal renal function) Didanosine	No Dose Adjustment	Boceprevir: Both clarithromycin and boceprevir are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when co-administered. No dose adjustments are necessary for patients with normal renal function (see Victrelis^® prescribing information).
Zidovudine		Zidovudine: Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Administration of clarithromycin and zidovudine should be separated by at least two hours [see Pharmacokinetics (12.3)]. The impact of co-administration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated.
Calcium Channel Blockers:
Verapamil	Use With Caution	Verapamil: Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, [see Warnings and Precautions (5.4)].
Amlodipine Diltiazem		Amlodipine, Diltiazem: [See Warnings and Precautions (5.4)]
Nifedipine		Nifedipine: Nifedipine is a substrate for CYP3A. Clarithromycin and other macrolides are known to inhibit CYP3A. There is potential of CYP3A-mediated interaction between nifedipine and clarithromycin. Hypotension and peripheral edema were observed when clarithromycin was taken concomitantly with nifedipine [see Warnings and Precautions (5.4)].
Ergot Alkaloids:
Ergotamine Dihydroergotamine	Contraindicated	Ergotamine, Dihydroergotamine: Postmarketing reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4.6)].
Gastroprokinetic Agents:
Cisapride	Contraindicated	Cisapride: [See Contraindications (4.2)]
HMG-CoA Reductase Inhibitors:
Lovastatin Simvastatin	Contraindicated	Lovastatin, Simvastatin, Atorvastatin, Pravastatin, Fluvastatin: [See Contraindications (4.5) and Warnings and Precautions (5.4)]
Atorvastatin Pravastatin	Use With Caution
Fluvastatin	No Dose Adjustment
Hypoglycemic Agents:
Nateglinide Pioglitazone Repaglinide Rosiglitazone	Use With Caution	Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]
Insulin		Insulin: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]
Immunosuppressants:
Cyclosporine	Use With Caution	Cyclosporine: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine.
Tacrolimus		Tacrolimus: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with tacrolimus.
Phosphodiesterase inhibitors:
Sildenafil Tadalafil Vardenafil	Use With Caution	Sildenafil, Tadalafil, Vardenafil: Each of these phosphodiesterase inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant administration of clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil, or vardenafil will result in increased exposure of these phosphodiesterase inhibitors. Co-administration of these phosphodiesterase inhibitors with clarithromycin is not recommended. Increased systemic exposure of these drugs may occur with clarithromycin; reduction of dosage for phosphodiesterase inhibitors should be considered (see their respective prescribing information).
Proton Pump Inhibitors:
Omeprazole	No Dose Adjustment	Omeprazole: The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when coadministered with clarithromycin as a result of increased omeprazole exposures [see Pharmacokinetics (12.3)] (see also Omeprazole under “Drugs That Affect BIAXIN” in the table below).
Xanthine Derivatives:
Theophylline	Use With Caution	Theophylline: Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations [see Pharmacokinetics (12.3)]. Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range.
Triazolobenzodiazepines and Other Related Benzodiazepines:
Midazolam	Use With Caution	Midazolam: When oral midazolam is co-administered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated [see Warnings and Precautions (5.4) and Pharmacokinetics (12.3)].
Alprazolam Triazolam		Triazolam, Alprazolam: Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is co-administered with clarithromycin. There have been postmarketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested. In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines.
Temazepam Nitrazepam Lorazepam	No Dose Adjustment	Temazepam, Nitrazepam, Lorazepam: For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.
Cytochrome P450 Inducers:
Rifabutin	Use With Caution	Rifabutin: Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis (see Rifabutin under “Drugs That Affect BIAXIN” in the table below).
Other Drugs Metabolized by CYP3A:
Alfentanil Bromocriptine Cilostazol Methylprednisole Vinblastine Phenobarbital St. John’s Wort	Use With Caution	There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort.
Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A:
Hexobarbital Phenytoin Valproate	Use With Caution	There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.
Drugs that Affect BIAXIN
Drug(s) that Affect the Pharmacokinetics of BIAXIN	Recommendation	Comments
Antifungals:
Itraconazole	Use With Caution	Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions (see also Itraconazole under “Drugs That Are Affected By BIAXIN” in the table above).
Antivirals:
Atazanavir	Use With Caution	Atazanavir: When clarithromycin is co-administered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology (12.3)]. Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.
Ritonavir (in patients with decreased renal function)		Ritonavir: Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with ritonavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium [see Pharmacokinetics (12.3)]. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.
Saquinavir (in patients with decreased renal function)		Saquinavir: When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (refer to ritonavir above) [see Pharmacokinetics (12.3)].
Etravirine		Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.
Saquinavir (in patients with normal renal function)	No Dose Adjustment
Ritonavir (in patients with normal renal function)
Proton Pump Inhibitors:
Omeprazole	Use With Caution	Omeprazole: Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole [see Pharmacokinetics (12.3)].
Miscellaneous Cytochrome P450 Inducers:
Efavirenz Nevirapine Rifampicin Rifabutin Rifapentine	Use With Caution	Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are Affected By BIAXIN” in the table above).

Table name:

albuterol, systemic and inhaled	mebendazole
amoxicillin	medroxyprogesterone
ampicillin, with or without	methylprednisolone
sulbactam	metronidazole
atenolol	metoprolol
azithromycin	nadolol
caffeine, dietary ingestion	nifedipine
cefaclor	nizatidine
co-trimoxazole (trimethoprim and sulfamethoxazole)	norfloxacin
co-trimoxazole (trimethoprim and sulfamethoxazole)	ofloxacin
diltiazem	omeprazole
dirithromycin	prednisone, prednisolone
enflurane	ranitidine
famotidine	rifabutin
felodipine	roxithromycin
finasteride	Sorbitol (purgative doses do not inhibit
hydrocortisone	theophylline absorption)
isoflurane	sucralfate
isoniazid	terbutaline, systemic
isradipine	terfenadine
influenza vaccine	tetracycline
ketoconazole	tocainide
lomefloxacin

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Table 9: Summary of Effect of Coadministered Drugs on Exposure to LATUDA in Healthy Subjects or Patients with Schizophrenia
Coadministered drug	Dose schedule		Effect on LATUDA pharmacokinetics		Recommendation
	Coadministered drug	LATUDA	C _max	AUC
Ketoconazole (strong CYP3A4 inhibitor)	400 mg/day for 5 days	10 mg single dose	6.9-times LATUDA alone	9-times LATUDA alone	Should not be coadministered with LATUDA
Diltiazem (moderate CYP3A4 inhibitor)	240 mg/ day for 5 days	20 mg single dose	2.1- times LATUDA alone	2.2- times LATUDA alone	LATUDA dose should not exceed 40 mg/day if coadministered
Rifampin (strong CYP3A4 inducer)	600 mg/day for 8 days	40 mg single dose	1/7^th of LATUDA alone	1/5^th of LATUDA alone	Should not be coadministered with LATUDA
Lithium	600 mg BID for 8 days	120 mg/day for 8 days	0.9-times LATUDA alone	1.1- times LATUDA alone	No LATUDA dose adjustment required.

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

Table name:

Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
	? CBZ epoxide	May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

Table name:

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C Protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Antibiotics	Antineoplastics	Antifungals	Anti-inflammatory Drugs
ciprofloxacin gentamicin tobramycin vancomycin trimethoprim with sulfamethoxazole	melphalan	amphotericin B ketoconazole	azapropazon colchicine diclofenac naproxen sulindac
Gastrointestinal Agents	Immunosuppressives		Other Drugs
cimetidine ranitidine	tacrolimus		fibric acid derivatives (e.g. bezafibrate, fenofibrate) methotrexate

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
albuterol,	famotidine	nizatidine
systemic and inhaled	felodipine	norfloxacin
amoxicillin	finasteride	ofloxacin
ampicillin,	hydrocortisone	omeprazole
with or without	isoflurane	prednisone, prednisolone
sulbactam	isoniazid	ranitidine
atenolol	isradipine	rifabutin
azithromycin	influenza vaccine	roxithromycin
caffeine,	ketoconazole	sorbitol
dietary digestion	lomefloxacin	(purgative doses do not
cefaclor	mebendazole	inhibit theophylline
co-trimoxazole	medroxyprogesterone	absorption)
(trimethoprim and	methylprednisolone	sucralfate
sulfamethoxazole)	metronidazole	terbutaline, systemic
diltiazem	metoprolol	terfenadine
dirithromycin	nadolol	tetracycline
enflurane	nifedipine	tocainide

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Table 13 Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
↓ = Decreased (induces lamotrigine glucuronidation)
↑ = Increased (inhibits lamotrigine glucuronidation)
? = Conflicting data
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%
	? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold
	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.12, 7.3)

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, Posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine,danazol	Contraindicated with simvastatin
Verapamil, diltiazem	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products ( 2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents	Carefully monitor blood glucose ( 5.11, 7.3)

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Table 4: Clinically Relevant Interactions Affecting Omeprazole When Co-Administered with Other Drugs
CYP2C19 or CYP3A4 Inducers
Clinical Impact:	Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology ( 12.3)].
Intervention:	St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions ( 5.9)]. Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:	Increased exposure of omeprazole [see Clinical Pharmacology ( 12.3)].
Intervention:	Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole.

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Laboratory Tests	Effect of Salicylates
Thyroid Function	Decreased PBI; increased T₃ uptake
Urinary Sugar	False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5 g qd)
5 Hydroxyindole acetic acid	False negative with fluorometric test
Acetone, Ketone Bodies	False positive FeCl₃ in Gerhardt reaction; red color persists with boiling
17-OH corticosteroids	False reduced values with >4.8 g qd salicylate
Vanilmandelic Acid	False reduced values
Uric Acid	May increase or decrease depending on dose
Prothrombin	Decreased levels; slightly increased prothrombin time

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Drugs that Affect Renal Function	A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics	Dofetilide	Concomitant administration with digoxin was associated with a higher rate of Torsades de pointes.
	Sotalol	Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
	Dronedarone	Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog	Teriparatide	Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement	Thyroid	Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics	Epinephrine Norepinephrine Dopamine	Can increase the risk of cardiac arrhythmias.
Neuromuscular Blocking Agents	Succinylcholine	May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements	Calcium	If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers		Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.12, 7.3)

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cation or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products.
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agent	Carefully monitor blood glucose (5.11, 7.3)

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Classes of Drugs
Adrenal Cortical Steroid Inhibitors Antacids Antianxiety Agents Antiarrhythmics† Antibiotics† Anticonvulsants† Antidepressants† Antihistamines Antineoplastics†	Antipsychotic Medications Antithyroid Drugs† Barbiturates Diuretics† Enteral Nutritional Supplements Fungal Medications, Systemic† Gastric Acidity and Peptic Ulcer Agents† Hypnotics†	Hypolipidemics† Bile Acid-Binding Resins† HMG-CoA Reductase Inhibitors† Immunosuppressives Oral Contraceptives, Estrogen Containing Selective Estrogen Receptor Modulators Steroids, Adrenocortical† Tuberculosis Agents† Vitamins†

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Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs that Interfere with Hemostasis
Clinical Impact:	Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of MOBIC with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention:	Concomitant use of MOBIC and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. MOBIC is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, or Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of MOBIC and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of MOBIC and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention:	During concomitant use of MOBIC with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology (12.3)].
Intervention:	During concomitant use of MOBIC and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of MOBIC and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of MOBIC and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention:	During concomitant use of MOBIC and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention:	The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of MOBIC and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of MOBIC and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.
Kayexalate® (sodium polystyrene sulfonate)
Clinical Impact:	Cases of intestinal necrosis (possibly fatal) have been described in patients who received concomitant sorbitol and Kayexalate® (sodium polystyrene sulfonate). Due to the presence of sorbitol in MOBIC Oral Suspension, use with Kayexalate® is not recommended.
Intervention:	The concomitant use of MOBIC Oral Suspension with Kayexalate® is not recommended.

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Table 7: Summary of AED Interactions with Oxcarbazepine
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400-2000	900	nc nc denotes a mean change of less than 10%	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100-150	600-1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250-500	600-1800 >1200-2400	nc Pediatrics up to 40% increase Mean increase in adults at high oxcarbazepine doses [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400-2800	600-1800	nc	18% decrease [CI: 13% decrease, 40% decrease]

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Table 3: Clinically Important Drug Interactions with Repaglinide Tablets
Gemfibrozil
Clinical Impact:	Gemfibrozil significantly increased repaglinide exposures by 8.1 fold [see Clinical Pharmacology (12.3)].
Intervention:	Do not administer repaglinide tablets to patients receiving gemfibrozil [see Contraindications (4)].
Clopidogrel
Clinical Impact:	Clopidogrel increased repaglinide exposures by 3.9 to 5.1 fold [see Clinical Pharmacology (12.3)].
Intervention:	Avoid concomitant use of repaglinide tablets with clopidogrel. If concomitant use can not be avoided, initiate repaglinide tablets at 0.5 mg before each meal and do not exceed a total daily dose of 4 mg [see Dosage and Administration (2.3)]. Increased frequency of glucose monitoring may be required during concomitant use.
Cyclosporine
Clinical Impact:	Cyclosporine increased low dose repaglinide exposures by 2.5 fold [see Clinical Pharmacology (12.3)].
Intervention:	Daily maximum repaglinide tablets dose should be limited to 6 mg, and increased frequency of glucose monitoring may be required when repaglinide tablets are co-administered with cyclosporine.
CYP2C8 and CYP3A4 Inhibitors
Intervention:	Repaglinide tablets dose reductions and increased frequency of glucose monitoring may be required when co-administered.
Examples:	Drugs that are known to inhibit CYP3A4 include antifungal agents (ketoconazole, itraconazole) and antibacterial agents (clarithromycin, erythromycin). Drugs that are known to inhibit CYP2C8 include trimethoprim, gemfibrozil, montelukast, deferasirox, and clopidogrel.
CYP2C8 and CYP3A4 Inducers
Intervention:	Repaglinide tablets dose increases and increased frequency of glucose monitoring may be required when co-administered.
Examples:	Drugs that induce the CYP3A4 and/or 2C8 enzyme systems include rifampin, barbiturates, and carbamezapine.
Drugs That May Increase the Risk of Hypoglycemia
Intervention:	Repaglinide tablets dose reductions and increased frequency of glucose monitoring may be required when co-administered.
Examples:	Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, nonsteroidal anti-inflammatory agents (NSAIDs), pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics
Drugs That May Decrease the Blood Glucose Lowering Effect of Repaglinide Tablets
Intervention:	Repaglinide tablets dose increases and increased frequency of glucose monitoring may be required when co-administered.
Examples:	Atypical antipsychotics (e.g., olanzapine and clozapine), calcium channel antagonists, corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones
Drugs That May Blunt Signs and Symptoms of Hypoglycemia
Intervention:	Increased frequency of glucose monitoring may be required when repaglinide tablets are co-administered with these drugs.
Examples:	Beta-blockers, clonidine, guanethidine, and reserpine

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitors (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C Protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
*Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	C _max
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing.
	20 mg/day	4 mg/day	1.6	-	Do not exceed 8 mg/day
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers)
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Table 4. Mean (95% C.I.) maximal change in baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in healthy volunteers on daily alpha-blocker therapy
		Dosing of Vardenafil and Alpha-Blocker Separated by 6 Hours		Simultaneous dosing of Vardenafil and Alpha-Blocker
Alpha-Blocker		Vardenafil 10 mg Placebo-Subtracted	Vardenafil 20 mg Placebo-Subtracted	Vardenafil 10 mg Placebo-Subtracted	Vardenafil 20 mg Placebo-Subtracted
Terazosin 10 mg daily	Standing SBP	-7 (-10, -3)	-11 (-14, -7)	-23 (-31, 16) Due to the sample size, confidence intervals may not be an accurate measure for these data. These values represent the range for the difference.	-14 (-33, 11)
Terazosin 10 mg daily	Supine SBP	-5 (-8, -2)	-7 (-11, -4)	-7 (-25, 19)	-7 (-31, 22)
Tamsulosin 0.4 mg daily	Standing SBP	-4 (-8, -1)	-8 (-11, -4)	-8 (-14, -2)	-8 (-14, -1)
	Supine SBP	-4 (-8, 0)	-7 (-11, -3)	-5 (-9, -2)	-3 (-7, 0)

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin	Monitor phenytoin level (7)
Methotrexate	Monitor for methotrexate toxicity (7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased Ciprofloxacin Tablets, USP absorption. Take 2 hours before or 6 hours after Ciprofloxacin Tablets, USP (7)

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Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)].
Examples:	Benzodiazepines and other sedative hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue morphine sulfate extended-release tablets if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.6)].
Intervention:	Do not use morphine sulfate extended-release tablets in patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of morphine sulfate extended-release tablets and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of morphine sulfate extended-release tablets and/or the muscle relaxant as necessary.
Cimetidine
Clinical Impact:	The concomitant use of cimetidine can potentiate morphine effects and increase risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of morphine sulfate extended-release tablets and/or cimetidine as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when morphine sulfate extended-release tablets are used concomitantly with anticholinergic drugs.
P-Glycoprotein (P-gp) Inhibitors
Clinical Impact:	The concomitant use of PGP-inhibitors can increase the exposure to morphine by about two-fold and can increase risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of morphine sulfate extended-release tablets and/or the PGP-inhibitor as necessary.
Example:	quinidine

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AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Drugs That Interfere with Hemostasis
Clinical Impact:	• Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	• During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

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Table 7 Summary of AED Interactions with Oxcarbazepine Tablets
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Tablets Dose (mg/day)	Influence of Oxcarbazepine Tablets on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
¹ nc denotes a mean change of less than 10% ² Pediatrics ³ Mean increase in adults at high oxcarbazepine tablets doses
Carbamazepine	400-2000	900	nc¹	40% decrease [CI:17% decrease, 57% decrease]
Phenobarbital	100-150	600-1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI:12% decrease, 51% decrease]
Phenytoin	250-500	600-1800 >1200-2400	nc^1,2 up to 40% increase³ [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400-2800	600-1800	nc¹	18% decrease [CI:13% decrease, 40% decrease]

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Drugs That Interfere with Hemostasis
Clinical Impact:	Mefenamic acid and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of mefenamic acid and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of mefenamic acid with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity) .
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation) .
Intervention:	Concomitant use of mefenamic acid and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Mefenamic acid is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
Clinical Impact:	In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of mefenamic acid and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.
	During concomitant use of mefenamic acid and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia).
	When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention	During concomitant use of mefenamic acid with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact:	The concomitant use of mefenamic acid with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of mefenamic acid and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of mefenamic acid and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of mefenamic acid and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of mefenamic acid and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of mefenamic acid and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of mefenamic acid with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS;Gastrointestinal Bleeding, Ulceration andPerforation).
Intervention:	The concomitant use of mefenamic acid with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of mefenamic acid and pemetrexed may increase the risk of pemetrexedassociated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of mefenamic acid and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.
	NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.
	In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacid
Clinical Impact:	In a single dose study (n= 6), ingestion of an antacid containing 1.7-gram of magnesium hydroxide with 500-mg of mefenamic acid increased the C _max and AUC of mefenamic acid by 125% and 36%, respectively.
Intervention:	Concomitant use of mefenamic acid and antacids is not generally recommended because of possible increased adverse events.

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Figure 7: Mean Standing Systolic Blood Pressure Change from Baseline

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Table 4: Clinically Significant Drug Interactions with ABSTRAL
Inhibitors of CYP3A4
Clinical Impact:	The concomitant use of ABSTRAL and CYP3A4 inhibitors can increase the plasma concentration of fentanyl resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of ABSTRAL is achieved [see Warnings and Precautions (5.3)]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to fentanyl.
Intervention:	If concomitant use is necessary, consider dosage reduction of ABSTRAL until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the ABSTRAL dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples:	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir) grapefruit juice.
CYP3A4 Inducers
Clinical Impact:	The concomitant use of ABSTRAL with CYP3A4 inducers can decrease the plasma concentrations of fentanyl [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of withdrawal syndrome in patients who have developed physical dependence to fentanyl [see Warnings and Precautions (5.6)] After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention:	If concomitant use is necessary, consider increasing the ABSTRAL dosage until stable drug effects are achieved Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider ABSTRAL dosage reduction and monitor for signs of respiratory depression.
Examples:	rifampin, carbamazepine, phenytoin
Benzodiazepines and other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation, [see Warnings and Precautions (5.4)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions 5.10].
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue ABSTRAL if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.10)] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.1)].
Intervention:	The use of ABSTRAL is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of ABSTRAL and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Fentanyl may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of ABSTRAL and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on bloodpressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motilitywhen ABSTRAL is used concomitantly with anticholinergic drugs.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. ₄ ₃
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT , is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. ₄ ₄ ₄ ₄ ₃ ₄ ₄ ₄
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. ₄
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T to T , leading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T and T levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). ₄ ₃ ₃ ₄ ₃ ₄ ₃ ₄ ₃ ₄
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of I, I, and Tc. ¹²³ ¹³¹ ^99m
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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DRUG	DESCRIPTION OF INTERACTION
Sulfonylureas	Hypoglycemia potentiated.
Methotrexate	Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants	Increased bleeding.

Table 5: Established Drug Interactions Based on Studies with VIDEX EC or Studies with Buffered Formulations of Didanosine and Expected to Occur with VIDEX EC
Drug	Effect	Clinical Comment
↑ Indicates increase. ↓ Indicates decrease. ^a Coadministration of didanosine with food decreases didanosine concentrations. Thus, although not studied, it is possible that coadministration with heavier meals could reduce didanosine concentrations further.
ganciclovir	↑ didanosine concentration	If there is no suitable alternative to ganciclovir, then use in combination with VIDEX EC with caution. Monitor for didanosine-associated toxicity.
methadone	↓ didanosine concentration	If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is VIDEX EC. Patients should be closely monitored for adequate clinical response when VIDEX EC is coadministered with methadone, including monitoring for changes in HIV RNA viral load. Do not coadminister methadone with VIDEX pediatric powder due to significant decreases in didanosine concentrations.
nelfinavir	No interaction 1 hour after didanosine	Administer nelfinavir 1 hour after VIDEX EC.
tenofovir disoproxil fumarate	↑ didanosine concentration	A dose reduction of VIDEX EC to the following dosage once daily taken together with tenofovir disoproxil fumarate and a light meal (400 kcalories or less and 20% fat or less) or in the fasted state is recommended.^a

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Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
*Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio^*)		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	C_max
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cation or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products.
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agent	Carefully monitor blood glucose (5.11, 7.3)

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Table 14: Clinically Important Drug Interactions: Effect of other Drugs on Guanfacine Extended-Release
Concomitant Drug Name or Drug Class	Clinical Rationale and Magnitude of Drug Interaction	Clinical Recommendation
Strong and moderate CYP3A4 inhibitors, e.g., ketoconazole, fluconazole	Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in an increase in exposure	Consider dose reduction [see Dosage and administration ( 2.7 )]
Strong and moderate CYP3A4 inducers, e.g., rifampin, efavirenz	Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in a decrease in exposure	Consider dose increase [see Dosage and administration ( 2.7 )]

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Table 3 Effects of Other Drugs on Paroxetine
Concomitant Drug Name	Effect of Concomitant Drug on Paroxetine	Clinical Recommendations
Phenobarbital	Decreased paroxetine exposure
Phenytoin	Decreased paroxetine exposure
Fosamprenavir/ Ritonavir	Decreased plasma concentration of paroxetine	No dose adjustment for BRISDELLE. Monitor clinical effect of BRISDELLE.
Cimetidine	Increased plasma concentration of paroxetine

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CYP3A Inhibitors
Clinical Impact	Paricalcitol is partially metabolized by CYP3A. Hence, exposure of paricalcitol will increase upon coadministration with strong CYP3A inhibitors such as but not limited to: boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole.
Intervention	Dose adjustment of Paricalcitol capsules may be necessary. Monitor closely for iPTH and serum calcium concentrations, if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor.
Cholestyramine
Clinical Impact	Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of paricalcitol.
Intervention	Recommend to take Paricalcitol capsules at least 1 hour before or 4 to 6 hours after taking cholestyramine (or at as great an interval as possible) to avoid impeding absorption of paricalcitol.
Mineral Oil
Clinical Impact	Mineral oil or other substances that may affect absorption of fat may influence the absorption of paricalcitol.
Intervention	Recommend to take Paricalcitol capsules at least 1 hour before or 4 to 6 hours after taking mineral oil (or at as great an interval as possible) to avoid affecting absorption of paricalcitol.

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AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase ^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide ^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Interacting Drug	Interaction
Multivalent cationcontaining products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.12, 7.3)

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
↓= Decreased (induces lamotrigine gluronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ?= Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
	? CBZ epoxide	May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Drug	Description
Heparin	Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients
Pyrazinamide	Inhibits pyrazinamide-induced hyperuricemia
Uricosuric Agents	Effect of probenecid, sulfinpyrazone and phenylbutazone inhibited

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Table 1: Clinically Significant Drug Interactions with Oxycodone HCl
Inhibitors of CYP3A4 and CYP2D6
Clinical Impact:	The concomitant use of oxycodone HCl and CYP3A4 inhibitors can increase the plasma concentration of oxycodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of oxycodone HCl and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of oxycodone HCl is achieved [see Warnings and Precautions (5.4)]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the oxycodone plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to oxycodone.
Intervention:	If concomitant use is necessary, consider dosage reduction of oxycodone HCl until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the oxycodone HCl dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples:	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir).
CYP3A4 Inducers
Clinical Impact:	The concomitant use of oxycodone HCl and CYP3A4 inducers can decrease the plasma concentration of oxycodone [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to oxycodone [see Warnings and Precautions (5.12)]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the oxycodone plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention:	If concomitant use is necessary, consider increasing the oxycodone HCl dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider oxycodone HCl dosage reduction and monitor for signs of respiratory depression.
Examples:	Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.5)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Adverse Reactions (6.2)].
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue oxycodone HCl if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
Intervention:	The use of oxycodone HCl is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of oxycodone HCl and/or may precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use
Examples:	Butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Oxycodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of oxycodone HCl and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of dismissed diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant risk of anticholinergic drugs may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when oxycodone HCl is used concurrently with anticholinergic drugs.

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Factors	Dosage Adjustments for Aripiprazole
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors	Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double usual dose over 1 to 2 weeks

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Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine concentrations approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine and carbamazepine epoxide	? carbamazepine epoxide	May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2) ].
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.9) ].
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.11) and Use in Specific Populations (8.5) ].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs [see Adverse Reactions (6.1) ].
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions (5.16) ].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution Two-fold increase in exposure	Monitor for sildenafil toxicity [see Clinical Pharmacology (12.3) ].
Duloxetine	Avoid Use Five-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx^®(didanosine) chewable/ buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2.4) ].	Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

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Table 3: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in BPH patients on stable alpha-blocker therapy with tamsulosin 0.4 or 0.8 mg daily (Study 2)
	Vardenafil 10 mg Placebo-subtracted	Vardenafil 20 mg Placebo-subtracted
Standing SBP	-4 (-6.8, -0.3)	-4 (-6.8, -1.4)
Supine SBP	-5 (-8.2, -0.8)	-4 (-6.3, -1.8)

Table name:

Interacting Drug	Interaction
Drugs known to prolong QT interval (e.g., Class IA and Class III antiarrhythmic agents).	Quinine sulfate prolongs QT interval, ECG abnormalities including QT prolongation and Torsades de Pointes. Avoid concomitant use (5.3).
Other antimalarials (e.g., halofantrine, mefloquine).	ECG abnormalities including QT prolongation. Avoid concomitant use (5.3, 7.2).
CYP3A4 inducers or inhibitors	Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine (7.1).
CYP3A4 and CYP2D6 substrates	Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the co-administered drug (7.2).
Digoxin	Increased digoxin plasma concentration (5.8, 7.1).

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Table 8: Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C_max and AUC_τ)	Recommendations for Drug Dosage Adjustment/Comments
SirolimusResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (400 mg q24h)Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (300 mg q24h) (CYP3A4 Inhibition)	Slight Increase in AUC_τ	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)(CYP3A4 Inhibition)	No Significant Effect of Voriconazole on Ritonavir C_max or AUC_τ	Contraindicated because of significant reduction of voriconazole C_max and AUC_τ

Low-dose Ritonavir (100 mg q12h)	Slight Decrease in Ritonavir C_max and AUC_τ	Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole C_max and AUC_τ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated
Cyclosporine (CYP3A4 Inhibition)	AUC_τ Significantly Increased; No Significant Effect on C_max	When initiating therapy with VFEND in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
MethadoneResults based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30–100 mg q24h) (CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7)]
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see Drug Interactions (7)].
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7)].
NSAIDsNon-Steroidal Anti-Inflammatory Drug including. ibuprofen and diclofenac (CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [see Drug Interactions (7)].
Tacrolimus (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)	Increased	Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects on Indinavir Exposure	No dosage adjustment for indinavir when coadministered with VFEND
	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.
Everolimus (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Concomitant administration of voriconazole and everolimus is not recommended.

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Table 9. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug Name	Effect on Concentration of Lopinavir or Concomitant Drug	Clinical Comments
HIV-1 Antiviral Agents
Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz, nevirapine	↓ lopinavir	KALETRA dose increase is recommended in all patients [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)]. Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz. Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz. KALETRA should not be administered once daily in combination with efavirenz or nevirapine [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine	↑ lopinavir	Appropriate doses of the combination with respect to safety and efficacy have not been established.
Nucleoside Reverse Transcriptase Inhibitor: didanosine		KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).
Nucleoside Reverse Transcriptase Inhibitor: tenofovir	↑ tenofovir	KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitor: abacavir zidovudine	↓ abacavir ↓ zidovudine	KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.
HIV-1 Protease Inhibitor: amprenavir*	↑ amprenavir ↓ lopinavir	KALETRA should not be administered once daily in combination with amprenavir [see Dosage and Administration (2.1)].
HIV-1 Protease Inhibitor: fosamprenavir/ritonavir	↓ amprenavir ↓ lopinavir	An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: indinavir*	↑ indinavir	Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily [see Clinical Pharmacology (12.3)]. KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor: nelfinavir*	↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir	KALETRA should not be administered once daily in combination with nelfinavir [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
HIV-1 Protease Inhibitor: ritonavir*	↑ lopinavir	Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: saquinavir*	↑ saquinavir	The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor: tipranavir	↓ lopinavir AUC and C_min	KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily).
HIV CCR5 – Antagonist: maraviroc	↑ maraviroc	Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry^® (maraviroc).
Other Agents
Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), quinidine	↑ antiarrhythmics	Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.
Anticancer Agents: vincristine, vinblastine, dasatinib, nilotinib	↑ anticancer agents	Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents. For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.
Anticoagulant: warfarin		Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: carbamazepine, phenobarbital, phenytoin	↓ lopinavir ↓ phenytoin	KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
Antidepressant: bupropion	↓ bupropion ↓ active metabolite, hydroxybupropion	Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant: trazodone	↑ trazodone	Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-infective: clarithromycin	↑ clarithromycin	For patients with renal impairment, the following dosage adjustments should be considered: • For patients with CL_CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. • For patients with CL_CR < 30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary.
Antifungals: ketoconazole*, itraconazole, voriconazole	↑ ketoconazole ↑ itraconazole ↓ voriconazole	High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended. Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients.
Anti-gout: colchicine	↑ colchicine	Patients with renal or hepatic impairment should not be given colchicine with KALETRA. Treatment of gout flares-co-administration of colchicine in patients on KALETRA: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on KALETRA: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial: rifabutin*	↑ rifabutin and rifabutin metabolite	Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antimycobacterial: rifampin	↓ lopinavir	May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone [see Clinical Pharmacology (12.3) for magnitude of interaction].
Antiparasitic: atovaquone	↓ atovaquone	Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Benzodiazepines: parenterally administered midazolam	↑ midazolam	Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam [see Contraindications (4)]. If KALETRA is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Calcium Channel Blockers: dihydropyridine, felodipine, nifedipine, nicardipine	↑ dihydropyridine calcium channel blockers	Caution is warranted and clinical monitoring of patients is recommended.
Contraceptive: ethinyl estradiol*	↓ ethinyl estradiol	Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.
Corticosteroid: dexamethasone	↓ lopinavir	Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly.
disulfiram/metronidazole		KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Endothelin Receptor Antagonists: bosentan	↑ bosentan	Co-administration of bosentan in patients on KALETRA: In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Co-administration of KALETRA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA. After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin	↑ atorvastatin ↑ rosuvastatin	Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day. See Drugs with No Observed or Predicted Interactions with KALETRA ( 7.4 ) and Clinical Pharmacology (12.3) for drug interaction data with other HMG-CoA reductase inhibitors.
Immunosuppressants: cyclosporine, tacrolimus, rapamycin	↑ immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Inhaled Steroid: fluticasone	↑ fluticasone	Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect.
Long-acting beta-adrenoceptor Agonist: salmeterol	↑ salmeterol	Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic: methadone* fentanyl	↓ methadone ↑ fentanyl	Dosage of methadone may need to be increased when co-administered with KALETRA. Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA.
PDE5 inhibitors: sildenafil, tadalafil, vardenafil	↑ sildenafil ↑ tadalafil ↑ vardenafil	Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio^®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA [see Contraindications (4)]. The following dose adjustments are recommended for use of tadalafil (Adcirca^®) with KALETRA: Co-administration of ADCIRCA in patients on KALETRA: In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Co-administration of KALETRA in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: It is recommended not to exceed the following doses: • Sildenafil: 25 mg every 48 hours • Tadalafil: 10 mg every 72 hours • Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events.
* see Clinical Pharmacology (12.3) for magnitude of interaction.

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Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (C_max and AUC_τ after 200 mg q12h)	Recommendations for Voriconazole Dosage Adjustment/Comments
Rifampin* and Rifabutin^* (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (400 mg q24h)^† (CYP450 Induction) Efavirenz (300 mg q24h)^† (CYP450 Induction)	Significantly Reduced Slight Decrease in AUCτ	Contraindicated When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High dose Ritonavir (400 mg q12h)^† (CYP450 Induction) Low dose Ritonavir (100 mg q12h)^† (CYP450 Induction)	Significantly Reduced Reduced	Contraindicated Coadministration of voriconazole and low dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Long -acting Barbiturates (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Phenytoin^* (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John's Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives^† containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole^† (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIs^‡ (CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure) A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to voriconazole Careful assessment of voriconazole effectiveness

Table name:

Table 2: Clinically Significant Drug Interactions with Alfentanil HCl Injection
Inhibitors of CYP3A4 and CYP2D6
Clinical Impact:	The concomitant use of Alfentanil HCl Injection and CYP3A4 inhibitors can increase the plasma concentration of alfentanil, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of Alfentanil HCl Injection and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of Alfentanil HCl Injection is achieved [see Warnings and Precautions (5.4)]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the alfentanil plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to alfentanil.
Intervention:	If concomitant use is necessary, consider dosage reduction of Alfentanil HCl Injection until stable drug effects are achieved [see Dosage and Administration (2.2)]. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the Alfentanil HCl Injection dosage until stable drug effects are achieved [see Dosage and Administration (2.2)]. Monitor for signs of opioid withdrawal.
Examples:	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact:	The concomitant use of Alfentanil HCl Injection and CYP3A4 inducers can decrease the plasma concentration of alfentanil [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to alfentanil [see Warnings and Precautions (5.13)]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the alfentanil plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention:	If concomitant use is necessary, consider increasing the Alfentanil HCl Injection dosage until stable drug effects are achieved [see Dosage and Administration (2.2)]. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider Alfentanil HCl Injection dosage reduction and monitor for signs of respiratory depression.
Examples:	Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Diazepam administered immediately prior to or in conjunction with high doses of Alfentanil HCl Injection may produce vasodilation and hypotension, and may result in delayed recovery. Both the magnitude and duration of central nervous system and cardiovascular effects may be enhanced when Alfentanil HCl Injection is administered in combination with other CNS depressants such as barbiturates, tranquilizers, opioids, or inhalation general anesthetics. Postoperative respiratory depression may be enhanced or prolonged by these agents.
Intervention:	Monitor patients receiving Alfentanil HCl Injection and benzodiazepines or other CNS depressants for hypotension patients and prolonged respiratory depression and sedation. In such cases of combined treatment, the dose of one or both agents should be reduced. Limited clinical experience indicates that requirements for volatile inhalation anesthetics are reduced by 30 to 50% for the first sixty (60) minutes following alfentanil induction. [see Warnings and Precautions (5.2)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions (5.7)].
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Alfentanil HCl Injection if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors
Clinical Impact:	Severe and unpredictable potentiation of monoamine oxidase (MAO) inhibitors has been reported rarely with alfentanil. MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)]
Intervention:	When Alfentanil HCl Injection is administered to patients who have received MAO inhibitors within 14 days, monitor patients for hypertension and ensure ready availability of vasodilators and beta-blockers for the treatment of hypertension as needed.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of Alfentanil HCl Injection and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Alfentanil may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Alfentanil HCl Injection and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when Alfentanil HCl Injection is used concomitantly with anticholinergic drugs.
Cimetidine
Clinical Impact:	Cimetidine reduces the clearance of alfentanil, extending the duration of action.
Intervention:	Use smaller alfentanil doses for prolonged administration and monitor closely for respiratory depression and other effects of alfentanil.
Nitrous oxide
Clinical Impact:	Nitrous oxide has been reported to produce cardiovascular depression when given with higher doses of Alfentanil HCl Injection.
Intervention:	Monitor patients for signs of cardiovascular depression that may be greater than otherwise expected.

Table name:

edema hereditary coumarin resistance hyperlipemia

hypothyroidism nephrotic syndrome

Table name:

Table 7. Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C _max and AUC _τ )	Recommendations for Drug Dosage Adjustment/Comments
Sirolimus^* (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin^* (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (400 mg q24h)^** (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (300 mg q24h)^** (CYP3A4 Inhibition)	Slight Increase in AUC_τ	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)^**(CYP3A4 Inhibition)	No Significant Effect of Voriconazole on Ritonavir C_max or AUC_τ	Contraindicated because of significant reduction of voriconazole C_max and AUC_τ
Low-dose Ritonavir (100 mg q12h)^**	Slight Decrease in Ritonavir C_max and AUC_τ	Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole C_max and AUC_τ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated
Cyclosporine^* (CYP3A4 Inhibition)	AUC_τ Significantly Increased; No Significant Effect on C_max	When initiating therapy with voriconazole in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
Methadone^*** (CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7) ]
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see Drug Interactions (7) ].
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate- associated adverse events may be necessary [see Drug Interactions (7) ].
NSAIDs^**** including. ibuprofen and diclofenac (CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [see Drug Interactions (7) ].
Tacrolimus^* (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with voriconazole in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin^* (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)^**	Increased	Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin^* (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	Monitor PT or other suitable anti- coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole^* (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with voriconazole in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one- half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects on Indinavir Exposure	No dosage adjustment for indinavir when coadministered with voriconazole
	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIs^***** (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.
Everolimus	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Concomitant administration of voriconazole and everolimus is not recommended.

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( 2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents	Carefully monitor blood glucose ( 5.12, 7.3)

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Drugs that Affect Renal Function	A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics	Dofetilide	Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
	Sotalol	Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
	Dronedarone	Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog	Teriparatide	Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement	Thyroid	Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics	Epinephrine Norepinephrine Dopamine	Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents	Succinylcholine	May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements	Calcium	If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers		Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine (CBZ) and CBZ epoxide	? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2 fold.
Valproate	? valproate	Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

Table name: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.During concomitant use of celecoxib capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of celecoxib capsules and ACE-inhibitors or ARBs in patients who are elderly, volume- depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6) ]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.

1.
Drugs That Interfere with Hemostasis
Clinical Impact:	Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of celecoxib capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11) ].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2) ]. In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200-400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100-325 mg).
Intervention:	Concomitant use of celecoxib capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11) ]. Celecoxib capsules are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:
Intervention:
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of celecoxib capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6) ].
Digoxin
Clinical Impact:	The concomitant use of celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of celecoxib capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of celecoxib capsules and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Celecoxib capsules have no effect on methotrexate pharmacokinetics.
Intervention:	During concomitant use of celecoxib capsules and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of celecoxib capsules and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of celecoxib capsules and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2) ].
Intervention:	The concomitant use of celecoxib with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of celecoxib capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of celecoxib capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or inducers
Clinical Impact:	Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co‑-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib.
Intervention	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers [see Clinical Pharmacology (12.3) ].
CYP2D6 substrates
Clinical Impact:	In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs.
Intervention	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates [see Clinical Pharmacology (12.3) ].
Corticosteroids
Clinical Impact:	Concomitant use of corticosteroids with celecoxib capsules may increase the risk of GI ulceration or bleeding.
Intervention	Monitor patients with concomitant use of celecoxib capsules with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)].

Table name:

^a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. ^b = Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. NE = Not Evaluated
AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

Table name:

AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

Table name:

Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitors (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

Table name:

Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin	Monitor phenytoin level (7)
Methotrexate	Monitor for methotrexate toxicity (7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)

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Table 6. Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (C_max and AUC _τ after 200 mg q12h)	Recommendations for Voriconazole Dosage Adjustment/Comments
RifampinResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects and Rifabutin (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (400 mg q24h)Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects (CYP450 Induction) Efavirenz (300 mg q24h) (CYP450 Induction)	Significantly Reduced Slight Decrease in AUC_τ	Contraindicated When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High dose Ritonavir (400 mg q12h) (CYP450 Induction)	Significantly Reduced	Contraindicated
Low dose Ritonavir (100 mg q12h) (CYP450 Induction)	Reduced	Coadministration of voriconazole and low dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Long-acting Barbiturates (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Phenytoin (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John’s Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to voriconazole
	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Careful assessment of voriconazole effectiveness

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DRUG	DESCRIPTION OF INTERACTION
Sulfonylureas	Hypoglycemia potentiated.
Methotrexate	Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants	Increased bleeding.

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)	Do not exceed 40 mg atorvastatin daily

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Interacting Drug	Interaction
Multivalent cation-containing products including : antacids, sucralfate, multivitamins	Decreased moxifloxacin hydrochloride absorption. Take moxifloxacin hydrochloride tablets at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time/INR, and bleeding. (6, 7.2, 12.3)
Class IA and Class III antiarrhythmics:	Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.6, 7.5)
Antidiabetic agents	Carefully monitor blood glucose. (5.11, 7.3)

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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TABLE 2. Mean (± S.D.) Pharmacokinetic Parameters for Estradiol, Estrone, and Equilin Following Coadministration of Conjugated Estrogens 0.625 mg and Progesterone Capsules 200 mg for 12 Days to Postmenopausal Women
^a Total estrogens is the sum of conjugated and unconjugated estrogen.
	Conjugated Estrogens			Conjugated Estrogens plus Progesterone Capsules
Drug	C _max (ng/mL)	T _max (hr)	AUC _(0-24h) (ng × h/mL)	C _max (ng/mL)	T _max (hr)	AUC _(0-24h) (ng × h/mL)
Estradiol	0.037 ± 0.048	12.7 ± 9.1	0.676 ± 0.737	0.030 ± 0.032	17.32 ± 1.21	0.561 ± 0.572
Estrone Total ^a	3.68 ± 1.55	10.6 ± 6.8	61.3 ± 26.36	4.93 ± 2.07	7.5 ± 3.8	85.9 ± 41.2
Equilin Total ^a	2.27 ± 0.95	6.0 ± 4.0	28.8 ± 13.0	3.22 ± 1.13	5.3 ± 2.6	38.1 ± 20.2

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Table 7. Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (C_max and AUCτ after 200 mg q12h)	Recommendations for Voriconazole Dosage Adjustment/Comments
Rifampin* and Rifabutin* (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (400 mg q 24h) (CYP450 Induction) Efavirenz (300 mg q 24h) (CYP450 Induction)	Significantly Reduced Slight decrease in AUC_t	Contraindicated When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)** (CYP450 Induction)	Significantly Reduced	Contraindicated
Low-dose Ritonavir (100 mg q12h)** (CYP450 Induction)	Reduced	Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Phenytoin* (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John’s Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives** containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole** (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIs*** (CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to voriconazole
	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Careful assessment of voriconazole effectiveness

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Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.8)].
Benzodiazepines (e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.8)]	Monitor sedation and blood pressure. Adjust dose accordingly.

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Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
*Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	C_max
Enzyme (CYP2D6) inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not Needed

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Table 2: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 5 mg in BPH patients on stable alpha-blocker therapy (Study 1)
Alpha-Blocker		Simultaneous dosing of Vardenafil 5 mg and Alpha-Blocker, Placebo-Subtracted	Dosing of Vardenafil 5 mg and Alpha-Blocker Separated by 6 Hours, Placebo-Subtracted
Terazosin 5 or 10 mg daily	Standing SBP	-3 (-6.7, 0.1)	-4 (-7.4, -0.5)
Terazosin 5 or 10 mg daily	Supine SBP	-4 (-6.7, -0.5)	-4 (-7.1, -0.7)
Tamsulosin 0.4 mg daily	Standing SBP Supine SBP	-6 (-9.9, -2.1) -4 (-7.0, -0.8)	-4 (-8.3, -0.5) -5 (-7.9, -1.7)

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir )	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

Table name: Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3)]. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)]. There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.

•
Antiretrovirals
Clinical Impact:	The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
Intervention:	Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications (4)]. Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:	Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention:	Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact:	Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].
Intervention:	A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact:	Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)]. There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention:	Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6)].
Citalopram
Clinical Impact:	Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention:	Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:	Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].
Intervention:	Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:	Potential for increased exposure of phenytoin.
Intervention:	Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:	Increased exposure of diazepam [see Clinical Pharmacology (12.3)].
Intervention:	Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:	Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention:	Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:	Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:	Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)]. See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:	Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:	See Contraindications, Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact:	Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention:	Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:	Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10), Clinical Pharmacology (12.2)].
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:	Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact:	There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:	An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:	There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:	Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)	Do not exceed 40 mg atorvastatin daily

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^a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. ^b = Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. NE = Not Evaluated
AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Table 6. Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (C_max and AUCτ after 200 mg q12h)	Recommendations for Voriconazole Dosage Adjustment/Comments
Rifampin* and Rifabutin* (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (400 mg q 24h) (CYP450 Induction) Efavirenz (300 mg q 24h) (CYP450 Induction)	Significantly Reduced Slight decrease in AUC_t	Contraindicated When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)** (CYP450 Induction)	Significantly Reduced	Contraindicated
Low-dose Ritonavir (100 mg q12h)** (CYP450 Induction)	Reduced	Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Phenytoin* (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John’s Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives** containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole** (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIs*** (CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to voriconazole
	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Careful assessment of voriconazole effectiveness

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Table 8: Selected Drug Interactions in Adults
Concomitant Drug Class: Drug Name	Effect on Concentration of Raltegravir	Clinical Comment
Metal-Containing Antacids
aluminum and/or magnesium-containing antacids	↓	Coadministration or staggered administration of aluminum and/or magnesium hydroxide-containing antacids and ISENTRESS is not recommended.
Other Agents
rifampin	↓	The recommended dosage of ISENTRESS is 800 mg twice daily during coadministration with rifampin. There are no data to guide co-administration of ISENTRESS with rifampin in patients below 18 years of age [see Dosage and Administration (2.1)].

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Antibiotics	Anti-neoplastics	Antifungals	Anti-inflammatory Drugs	Gastrointestinal Agents	Immuno-suppressives	Other Drugs
ciprofloxacin gentamicin tobramycin vancomycin trimethoprim with sulfamethoxazole	melphalan	amphotericin B ketoconazole	azapropazon colchicine diclofenac naproxen sulindac	cimetidine ranitidine	tacrolimus	fibric acid derivatives (e.g., bezafibrate, fenofibrate) methotrexate

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Table 7: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
* Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects * Non-Nucleoside Reverse Transcriptase Inhibitors
Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (C_max and AUC _τ after 200 mg q12h)	Recommendations for Voriconazole Dosage Adjustment/Comments
Rifampin* and Rifabutin* (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (400 mg q24h) (CYP450 Induction) Efavirenz (300 mg q24h) (CYP450 Induction)	Significantly Reduced Slight Decrease in AUCτ	Contraindicated When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h) (CYP450 Induction) Low-dose Ritonavir (100 mg q12h) (CYP450 Induction)	Significantly Reduced Reduced	Contraindicated Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Phenytoin* (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John’s Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives** containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole** (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIs*** (CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure) A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to voriconazole Careful assessment of voriconazole effectiveness

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Table 2: Drug-Thyroidal Axis Interactions
	Drug or Drug Class		Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
		Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
		Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
		Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
		Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
		Amiodarone Iodide (including iodine- containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
	Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
	Drugs that may increase		Drugs that may decrease
	serum TBG concentration		serum TBG concentration
	Clofibrate		Androgens / Anabolic Steroids
	Estrogen-containing oral		Asparaginase
	contraceptives		Glucocorticoids
	Estrogens (oral)		Slow-Release Nicotinic Acid
	Heroin / Methadone
	5-Fluorouracil
	Mitotane
	Tamoxifen
	Drugs that may cause protein-binding site displacement
	Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)		Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
	Carbamazepine Hydantoins Phenobarbital Rifampin		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
	Drugs that may decrease T ₄ 5' - deiodinase activity
	Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)		Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, Ieading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
	Miscellaneous
	Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives		Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
	Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
	Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin		Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
	Cardiac Glycosides		Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
	Cytokines - Interferon-α - Interleukin-2		Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
	Growth Hormones - Somatrem - Somatropin		Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
	Ketamine		Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
	Methylxanthine Bronchodilators - (e.g., Theophylline)		Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
	Radiographic Agents		Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
	Sympathomimetics		Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
	Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics		These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 4. Sevelamer Drug Interactions
Oral drugs for which sevelamer did not alter the pharmacokinetics when administered concomitantly
Digoxin Enalapril Iron Metoprolol Warfarin
Oral drugs that have demonstrated interaction with sevelamer and are to be dosed separately from Renagel
	Dosing Recommendations
Ciprofloxacin	Take at least 2 hours before or 6 hours after sevelamer
Mycophenolate mofetil	Take at least 2 hours before sevelamer

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Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of aripiprazole with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.7)].
Benzodiazepines(e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.7)].	Monitor sedation and blood pressure. Adjust dose accordingly.

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline. Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol,	lomefloxacin
systemic and inhaled	mebendazole
amoxicillin	medroxyprogesterone
ampicillin,	methylprednisolone
with or without sulbactam	metronidazole
atenolol	metoprolol
azithromycin	nadolol
caffeine,	nifedipine
dietary ingestion	nizatidine
cefactor	norfloxacin
co-trimoxazole	ofloxacin
(trimethoprim and	omeprazole
sulfamethoxazole)	prednisone, prednisolone
diltiazem	ranitidine
dirithromycin	rifabutin
enflurane	roxithromycin
famotidine	sorbitol
felodipine	(purgative doses do not
finasteride	inhibit theophylline
hydrocortisone	absorption)
isoflurane	sucralfate
isoniazid	terbutaline, systemic
isradipine	terfenadine
influenza vaccine	tetracycline
ketoconazole	tocainide

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Table 25: Clinically Important Drug Interactions with ABILIFY:
Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of ABILIFY with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of ABILIFY alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of ABILIFY with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the ABILIFY dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of ABILIFY and carbamazepine decreased the exposure of aripiprazole compared to the use of ABILIFY alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of ABILIFY with a strong CYP3A4 inducer, consider increasing the ABILIFY dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.8) ].
Benzodiazepines (e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.8) ].	Monitor sedation and blood pressure. Adjust dose accordingly.

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Factors	Dosage Adjustment of Aripiprazole tablets
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
KnownCYP2D6Poor Metabolizersand strongCYP3A4 inhibitors	Administer a quarter of usualdose
StrongCYP2D6 or CYP3A4inhibitors	Administerhalf of usual dose
StrongCYP2D6andCYP3A4 inhibitors	Administer a quarter of usualdose
StrongCYP3A4inducers	Double usual doseover 1 to 2 weeks

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Table 9 Established and Other Potentially Significant Drug Interactions with Ganciclovir
Name of the Concomit a nt Drug	Change in the Concentration of Ganciclovir or Concomitant Drug	Clinical Comment
Zidovudine	↓ Ganciclovir ↑ Zidovudine	Zidovudine and Valganciclovir each have the potential to cause neutropenia and anemia
Probenecid	↑ Ganciclovir	Patients taking probenecid and Valganciclovir should be monitored for evidence of ganciclovir toxicity
Mycophenolate Mofetil (MMF)	↔ Ganciclovir (in patients with normal renal function) ↔ MMF (in patients with normal renal function)	Patients with renal impairment should be monitored carefully as levels of MMF metabolites and ganciclovir may increase
Didanosine	↓ Ganciclovir ↑ Didanosine	Patients should be closely monitored for didanosine toxicity

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
* Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9-Hydroxy- Risperidone Ratio*)		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	C_max	Risperidone Dose Recommendation
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Bleeding times
Clinical Impact:	Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention:	This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact:	The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention:	Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact:	Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention:	This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.

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Table 3 Effects of Other Drugs on Paroxetine
Concomitant Drug Name	Effect of Concomitant Drug on Paroxetine	Clinical Recommendations
Phenobarbital	Decreased paroxetine exposure
Phenytoin	Decreased paroxetine exposure
Fosamprenavir/ Ritonavir	Decreased plasma concentration of paroxetine	No dose adjustment for BRISDELLE. Monitor clinical effect of BRISDELLE.
Cimetidine	Increased plasma concentration of paroxetine

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Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine concentrations approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine and carbamazepine epoxide	? carbamazepine epoxide	May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)]
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.9)].
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.11) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs [see Adverse Reactions (6.1)].
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.16)].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution Two-fold increase in exposure	Monitor for sildenafil toxicity [see Clinical Pharmacology (12.3)].
Duloxetine	Avoid Use Five-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Caffeine/Xanthine Derivatives	Reduced clearance resulting in elevated levels and prolongation of serum half-life
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx^® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation- containing products administration [see Dosage and Administration (2.4)].	Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
		Potentiation of ciprofloxacin toxicity may occur.
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

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Factors	Dosage Adjustment of Aripiprazole tablets
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
KnownCYP2D6Poor Metabolizersand strongCYP3A4 inhibitors	Administer a quarter of usualdose
StrongCYP2D6 or CYP3A4inhibitors	Administerhalf of usual dose
StrongCYP2D6andCYP3A4 inhibitors	Administer a quarter of usualdose
StrongCYP3A4inducers	Double usual doseover 1 to 2 weeks

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Table 3: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in BPH patients on stable alpha-blocker therapy with tamsulosin 0.4 or 0.8 mg daily (Study 2)
	Vardenafil 10 mg Placebo-subtracted	Vardenafil 20 mg Placebo-subtracted
Standing SBP	-4 (-6.8, -0.3)	-4 (-6.8, -1.4)
Supine SBP	-5 (-8.2, -0.8)	-4 (-6.3, -1.8)

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Summary of AED interactions with topiramate (7.1).
AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400mg/day	13% decrease

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Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin dailyFor patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Table 8: Clinically Significant Drug Interactions with Clarithromycin
Drugs That Are Affected By Clarithromycin
Drug(s) with Pharmacokinetics Affected by Clarithromycin	Recommendation	Comments
Antiarrhythmics:
Disopyramide Quinidine Dofetilide Amiodarone Sotalol Procainamide	Not Recommended	Disopyramide, Quinidine: There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs [see Warnings and Precautions (5.3)]. Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine. There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.
Digoxin	Use With Caution	Digoxin: Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are co-administered, inhibition of Pgp by clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range.
Oral Anticoagulants:
Warfarin	Use With Caution	Oral anticoagulants: Spontaneous reports in the postmarketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously [see Warnings and Precautions (5.4)].
Antiepileptics:
Carbamazepine	Use With Caution	Carbamazepine: Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered. Increased serum concentrations of carbamazepine were observed in clinical trials with clarithromycin. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with carbamazepine.
Antifungals:
Itraconazole	Use With Caution	Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly (see also Itraconazole under “Drugs That Affect Clarithromycin” in the table below). Clarithromycin may increase the plasma concentrations of itraconazole. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions.
Fluconazole	No Dose Adjustment	Fluconazole: [see Pharmacokinetics (12.3)]
Anti-Gout Agents:
Colchicine (in patients with renal or hepatic impairment) Colchicine (in patients with normal renal and hepatic function)	Contraindicated Use With Caution	Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. The dose of colchicine should be reduced when co-administered with clarithromycin in patients with normal renal and hepatic function [see Contraindications (4.4) and Warnings and Precautions (5.4)].
Antipsychotics:
Pimozide	Contraindicated	Pimozide: [See Contraindications (4.2)]
Quetiapine		Quetiapine: Quetiapine is a substrate for CYP3A4, which is inhibited by clarithromycin. Co-administration with clarithromycin could result in increased quetiapine exposure and possible quetiapine related toxicities. There have been postmarketing reports of somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation during concomitant administration. Refer to quetiapine prescribing information for recommendations on dose reduction if co-administered with CYP3A4 inhibitors such as clarithromycin.
Antispasmodics:
Tolterodine (patients deficient in CYP2D6 activity)	Use With Caution	Tolterodine: The primary route of metabolism for tolterodine is via CYP2D6. However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when co-administered with clarithromycin.
Antivirals:
Atazanavir	Use With Caution	Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)].
Saquinavir (in patients with decreased renal function)		Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction (see Saquinavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)].
Ritonavir Etravirine		Ritonavir, Etravirine: (see Ritonavir and Etravirine under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)].
Maraviroc		Maraviroc: Clarithromycin may result in increases in maraviroc exposures by inhibition of CYP3A metabolism. See Selzentry^® prescribing information for dose recommendation when given with strong CYP3A inhibitors such as clarithromycin.
Boceprevir (in patients with normal renal function) Didanosine	No Dose Adjustment	Boceprevir: Both clarithromycin and boceprevir are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when co-administered. No dose adjustments are necessary for patients with normal renal function (see Victrelis^® prescribing information).
Zidovudine		Zidovudine: Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Administration of clarithromycin and zidovudine should be separated by at least two hours [see Pharmacokinetics (12.3)]. The impact of co-administration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated.
Calcium Channel Blockers:
Verapamil	Use With Caution	Verapamil: Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, [see Warnings and Precautions (5.4)].
Amlodipine Diltiazem		Amlodipine, Diltiazem: [See Warnings and Precautions (5.4)]
Nifedipine		Nifedipine: Nifedipine is a substrate for CYP3A. Clarithromycin and other macrolides are known to inhibit CYP3A. There is potential of CYP3A-mediated interaction between nifedipine and clarithromycin. Hypotension and peripheral edema were observed when clarithromycin was taken concomitantly with nifedipine [see Warnings and Precautions (5.4)].
Ergot Alkaloids:
Ergotamine Dihydroergotamine	Contraindicated	Ergotamine, Dihydroergotamine: Postmarketing reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4.6)].
Gastroprokinetic Agents:
Cisapride	Contraindicated	Cisapride: [See Contraindications (4.2)]
HMG-CoA Reductase Inhibitors:
Lovastatin Simvastatin	Contraindicated	Lovastatin, Simvastatin, Atorvastatin, Pravastatin, Fluvastatin: [See Contraindications (4.5) and Warnings and Precautions (5.4)]
Atorvastatin Pravastatin	Use With Caution
Fluvastatin	No Dose Adjustment
Hypoglycemic Agents:
Nateglinide Pioglitazone Repaglinide Rosiglitazone	Use With Caution	Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]
Insulin		Insulin: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]
Immunosuppressants:
Cyclosporine	Use With Caution	Cyclosporine: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine.
Tacrolimus		Tacrolimus: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with tacrolimus.
Phosphodiesterase inhibitors:
Sildenafil Tadalafil Vardenafil	Use With Caution	Sildenafil, Tadalafil, Vardenafil: Each of these phosphodiesterase inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant administration of clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil, or vardenafil will result in increased exposure of these phosphodiesterase inhibitors. Co-administration of these phosphodiesterase inhibitors with clarithromycin is not recommended. Increased systemic exposure of these drugs may occur with clarithromycin; reduction of dosage for phosphodiesterase inhibitors should be considered (see their respective prescribing information).
Proton Pump Inhibitors:
Omeprazole	No Dose Adjustment	Omeprazole: The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when coadministered with clarithromycin as a result of increased omeprazole exposures [see Pharmacokinetics (12.3)] (see also Omeprazole under “Drugs That Affect Clarithromycin” in the table below).
Xanthine Derivatives:
Theophylline	Use With Caution	Theophylline: Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations [see Pharmacokinetics (12.3)]. Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range.
Triazolobenzodiazepines and Other Related Benzodiazepines:
Midazolam	Use With Caution	Midazolam: When oral midazolam is co-administered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated [see Warnings and Precautions (5.4) and Pharmacokinetics (12.3)].
Alprazolam Triazolam		Triazolam, Alprazolam: Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is co-administered with clarithromycin. There have been postmarketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested. In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines.
Temazepam Nitrazepam Lorazepam	No Dose Adjustment	Temazepam, Nitrazepam, Lorazepam: For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.
Cytochrome P450 Inducers:
Rifabutin	Use With Caution	Rifabutin: Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis (see Rifabutin under “Drugs That Affect Clarithromycin” in the table below).
Other Drugs Metabolized by CYP3A:
Alfentanil Bromocriptine Cilostazol Methylprednisole Vinblastine Phenobarbital St. John’s Wort	Use With Caution	There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort.
Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A:
Hexobarbital Phenytoin Valproate	Use With Caution	There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.
Drugs that Affect Clarithromycin
Drug(s) that Affect the Pharmacokinetics of Clarithromycin	Recommendation	Comments
Antifungals:
Itraconazole	Use With Caution	Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions (see also Itraconazole under “Drugs That Are Affected By Clarithromycin” in the table above).
Antivirals:
Atazanavir	Use With Caution	Atazanavir: When clarithromycin is co-administered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology (12.3)]. Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.
Ritonavir (in patients with decreased renal function)		Ritonavir: Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with ritonavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium [see Pharmacokinetics (12.3)]. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.
Saquinavir (in patients with decreased renal function)		Saquinavir: When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (refer to ritonavir above) [see Pharmacokinetics (12.3)].
Etravirine		Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.
Saquinavir (in patients with normal renal function)	No Dose Adjustment
Ritonavir (in patients with normal renal function)
Proton Pump Inhibitors:
Omeprazole	Use With Caution	Omeprazole: Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole [see Pharmacokinetics (12.3)].
Miscellaneous Cytochrome P450 Inducers:
Efavirenz Nevirapine Rifampicin Rifabutin Rifapentine	Use With Caution	Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are Affected By Clarithromycin” in the table above).

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
↓= Decreased (induces lamotrigine glucuronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ? = Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine (CBZ) and CBZ epoxide	? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide Is not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 7 Summary of AED Interactions with Oxcarbazepine Tablets, USP
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Tablets Dose (mg/day)	Influence of Oxcarbazepine Tablets on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400-2000	900	nc nc denotes a mean change of less than 10%	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100-150	600-1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250-500	600-1800 >1200-2400	nc ^, Pediatrics up to 40% increase Mean increase in adults at high oxcarbazepine tablets, USP doses [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400-2800	600-1800	nc	18% decrease [CI: 13% decrease, 40% decrease]

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Interacting Drug	Interaction
Drugs known to prolong QT interval (e.g., Class IA and Class III antiarrhythmic agents).	QUALAQUIN prolongs QT interval, ECG abnormalities including QT prolongation and Torsades de Pointes. Avoid concomitant use (5.3).
Other antimalarials (e.g., halofantrine, mefloquine).	ECG abnormalities including QT prolongation. Avoid concomitant use (5.3, 7.2).
CYP3A4 inducers or inhibitors	Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine (7.1).
CYP3A4 and CYP2D6 substrates	Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the co-administered drug (7.2).
Digoxin	Increased digoxin plasma concentration (5.8, 7.1).

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
albuterol, systemic and inhaled	lomefloxacin
amoxicillin	mebendazole
ampicillin, with or without sulbactam	medroxyprogesterone
atenolol	methylprednisolone
azithromycin	metronidazole
caffeine, dietary ingestion	metoprolol
cefaclor	nadolol
co-trimoxazole (trimethoprim and sulfamethoxazole)	nifedipine
diltiazem	nizatidine
dirithromycin	norfloxacin
enflurane	ofloxacin
famotidine	omeprazole
felodipine	prednisone, prednisolone
finasteride	ranitidine
hydrocortisone	rifabutin
isoflurane	roxithromycin
isoniazid	sorbitol (purgative doses do not inhibit theophylline absorption)
isradipine	sucralfate
influenza vaccine	terbutaline, systemic
ketoconazole	terfenadine
	tetracycline
	tocainide
* Refer to PRECAUTIONS, Drug Interactions for information regarding table.

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Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)	VIAGRA 100 mg
Supine	7.9 (4.6, 11.1)
Standing	4.3 (-1.8,10.3)

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Table II. Clinically Significant Drug Interactions With Theophylline*
Drug	Type Of Interaction	Effect**

Adenosine	Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.

Alcohol	A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours.	30% increase

Allopurinol	Decreases theophylline clearance at allopurinol doses ≥600 mg/day.	25% increase

Aminoglutethimide	Increases theophylline clearance by induction of microsomal enzyme activity.	25% decrease

Carbamazepine	Similar to aminoglutethimide.	30% decrease

Cimetidine	Decreases theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase

Ciprofloxacin	Similar to cimetidine.	40% increase

Clarithromycin	Similar to erythromycin.	25% increase

Diazepam	Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.	Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.

Disulfiram	Decreases theophylline clearance by inhibiting hydroxylation and demethylation.	50% increase

Enoxacin	Similar to cimetidine.	300% increase

Ephedrine	Synergistic CNS effects.	Increased frequency of nausea, nervousness, and insomnia.

Erythromycin	Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.

Estrogen	Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.	30% increase

Flurazepam	Similar to diazepam.	Similar to diazepam.

Fluvoxamine	Similar to cimetidine.	Similar to cimetidine.

Halothane	Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.	Increased risk of ventricular arrhythmias.

Interferon, human recombinant alpha-A	Decreases theophylline clearance.	100% increase

Isoproterenol (I.V.)	Increases theophylline clearance.	20% decrease

Ketamine	Pharmacologic	May lower theophylline seizure threshold.

Lithium	Theophylline increases renal lithium clearance.	Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.

Lorazepam	Similar to diazepam.	Similar to diazepam.

Methotrexate (MTX)	Decreases theophylline clearance.	20% increase after low dose MTX, higher dose MTX may have a greater effect.

Mexiletine	Similar to disulfiram.	80% increase

Midazolam	Similar to diazepam.	Similar to diazepam.

Moricizine	Increases theophylline clearance.	25% decrease

Pancuronium	Theophylline may antagonize nondepolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.	Larger dose of pancuronium may be required to achieve neuromuscular blockade.

Pentoxifylline	Decreases theophylline clearance.	30% increase

Phenobarbital (PB)	Similar to aminoglutethimide.	25% decrease after two weeks of concurrent Phenobarbital.

Phenytoin	Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.	Serum theophylline and phenytoin concentrations decrease about 40%.

Propafenone	Decreases theophylline clearance and pharmacologic interaction.	40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.

Propranolol	Similar to cimetidine and pharmacologic interaction.	100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.

Rifampin	Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.	20 - 40% decrease

Sulfinpyrazone	Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.	20% decrease

Tacrine	Similar to cimetidine, also increases renal clearance of theophylline.	90% increase

Thiabendazole	Decreases theophylline clearance.	190% increase

Ticlopidine	Decreases theophylline clearance.	60% increase

Troleandomycin	Similar to erythromycin.	33 - 100% increase depending on troleandomycin dose.

Verapamil	Similar to disulfiram.	20% increase

* Refer to PRECAUTIONS , Drug Interactions for further information regarding table.
** Average effect on steady-state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.

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Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 4: Clinically Relevant Interactions Affecting Omeprazole When Co-Administered with Other Drugs
CYP2C19 or CYP3A4 Inducers
Clinical Impact:	Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology ( 12.3)].
Intervention:	St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions ( 5.9)]. Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:	Increased exposure of omeprazole [see Clinical Pharmacology ( 12.3)].
Intervention:	Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole.

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Drug	Description
Heparin	Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients
Pyrazinamide	Inhibits pyrazinamide-induced hyperuricemia
Uricosuric Agents	Effect of probenecid, sulfinpyrazone and phenylbutazone inhibited

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.10, 7.3)

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Table 5. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
↓ = Decreased (induces lamotrigine glucuronidation). ↑ = Increased (inhibits lamotrigine glucuronidation). ? = Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine concentrations approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
	? carbamazepine epoxide	May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
	? valproate	There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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TABLE 2. Mean (± S.D.) Pharmacokinetic Parameters for Estradiol, Estrone, and Equilin Following Coadministration of Conjugated Estrogens 0.625 mg and PROMETRIUM Capsules 200 mg for 12 Days to Postmenopausal Women
^a Total estrogens is the sum of conjugated and unconjugated estrogen.
	Conjugated Estrogens			Conjugated Estrogens plus PROMETRIUM Capsules
Drug	C_max (ng/mL)	T_max (hr)	AUC_(0-24h) (ng × h/mL)	C_max (ng/mL)	T_max (hr)	AUC_(0-24h) (ng × h/mL)
Estradiol	0.037 ± 0.048	12.7 ± 9.1	0.676 ± 0.737	0.030 ± 0.032	17.32 ± 1.21	0.561 ± 0.572
Estrone Total^a	3.68 ± 1.55	10.6 ± 6.8	61.3 ± 26.36	4.93 ± 2.07	7.5 ± 3.8	85.9 ± 41.2
Equilin Total^a	2.27 ± 0.95	6.0 ± 4.0	28.8 ± 13.0	3.22 ± 1.13	5.3 ± 2.6	38.1 ± 20.2

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Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
*Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	C _m _a _x
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing.
	20 mg/day	4 mg/day	1.6	-	Do not exceed 8 mg/day
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers)
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C Protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 2: Clinically Relevant Interactions Affecting Drugs Co-Administered with Rabeprazole Sodium Delayed-Release Tablets
Antiretrovirals
Clinical Impact:	The effect of PPI on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and nelfinavir) when used concomitantly with rabeprazole may reduce antiviral effect and promote the development of drug resistance. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with rabeprazole may increase toxicity. There are other antiretroviral drugs which do not result in clinically relevant interactions with rabeprazole.
Intervention:	Rilpivirine-containing products: Concomitant use with rabeprazole sodium delayed-release tablets is contraindicated [see Contraindications (4)]. See prescribing information. Atazanavir: See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with rabeprazole sodium delayed-release tablets. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir and monitor for potential saquinavir toxicities. Other antiretrovirals: See prescribing information.
Warfarin
Clinical Impact:	Increased INR and prothrombin time in patients receiving PPIs, including rabeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death [see Warnings and Precautions (5.2)].
Intervention:	Monitor INR and prothrombin time. Dose adjustment of warfarin may be needed to maintain target INR range. See prescribing information for warfarin.
Methotrexate
Clinical Impact:	Concomitant use of rabeprazole with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of methotrexate with PPIs have been conducted [see Warnings and Precautions (5.9)].
Intervention:	A temporary withdrawal of rabeprazole sodium delayed-release tablets may be considered in some patients receiving high dose methotrexate administration.
Digoxin
Clinical Impact:	Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention:	Monitor digoxin concentrations. Dose adjustment of digoxin may be needed to maintain therapeutic drug concentrations. See prescribing information for digoxin.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole, itraconazole)
Clinical Impact:	Rabeprazole can reduce the absorption of drugs due to its effect on reducing intragastric acidity.
Intervention:	Mycophenolate mofetil (MMF): Co-administration of PPIs in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving PPIs and MMF. Use rabeprazole sodium delayed-release tablets with caution in transplant patients receiving MMF. See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:	Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:	See Contraindications and Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.

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Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine concentrations approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine and carbamazepine epoxide	? carbamazepine epoxide	May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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Table 9. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug Name	Effect on Concentration of Lopinavir or Concomitant Drug	Clinical Comment
* see Clinical Pharmacology (12.3) for Magnitude of Interaction.
HIV-1 Antiviral Agents
Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz, nevirapine	↓ lopinavir	KALETRA dose increase is recommended in all patients [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)]. Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz. Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz. KALETRA should not be administered once daily in combination with efavirenz or nevirapine. [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine	↑ lopinavir	Appropriate doses of the combination with respect to safety and efficacy have not been established.
Nucleoside Reverse Transcriptase Inhibitor: didanosine		KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).
Nucleoside Reverse Transcriptase Inhibitor: tenofovir	↑ tenofovir	KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitor: abacavir zidovudine	↓ abacavir ↓ zidovudine	KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.
HIV-1 Protease Inhibitor: amprenavir*	↑ amprenavir ↓ lopinavir	KALETRA should not be administered once daily in combination with amprenavir. [see Dosage and Administration (2.1)].
HIV-1 Protease Inhibitor: fosamprenavir/ritonavir	↓ amprenavir ↓ lopinavir	An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: indinavir*	↑ indinavir	Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily [see Clinical Pharmacology (12.3)]. KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor: nelfinavir*	↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir	KALETRA should not be administered once daily in combination with nelfinavir. [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
HIV-1 Protease Inhibitor: ritonavir*	↑ lopinavir	Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: saquinavir*	↑ saquinavir	The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor: tipranavir	↓ lopinavir AUC and C_min	KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily).
HIV CCR5 – antagonist: maraviroc	↑ maraviroc	Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry® (maraviroc).
Other Agents
Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), and quinidine	↑ antiarrhythmics	Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.
Anticancer Agents: vincristine vinblastine	↑ anticancer agents	Concentrations of vincristine or vinblastine may be increased when co-administered with lopinavir/ritonavir (KALETRA) resulting in the potential for increased adverse events usually associated with these anticancer agents. Consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when lopinavir/ritonavir ( KALETRA) is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor.
Anticoagulant: warfarin		Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: carbamazepine, phenobarbital, phenytoin	↓ lopinavir ↓ phenytoin	KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
Antidepressant: bupropion	↓ bupropion ↓ active metabolite, hydroxybupropion	Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant: trazodone	↑ trazodone	Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-infective: clarithromycin	↑ clarithromycin	For patients with renal impairment, the following dosage adjustments should be considered: For patients with CL_CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CL_CR < 30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary.
Antifungals: ketoconazole*, itraconazole, voriconazole	↑ ketoconazole ↑ itraconazole ↓ voriconazole	High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended. Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients.
Antimycobacterial: rifabutin*	↑ rifabutin and rifabutin metabolite	Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antimycobacterial: rifampin	↓ lopinavir	May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone. [see Clinical Pharmacology (12.3) for magnitude of interaction].
Antiparasitic: atovaquone	↓ atovaquone	Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Benzodiazepines: parenterally administered midazolam	↑ midazolam	Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam [see Contraindications (4)]. If KALETRA is coadministered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Calcium Channel Blockers, dihydropyridine: e.g., felodipine, nifedipine, nicardipine	↑ dihydropyridine calcium channel blockers	Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid: dexamethasone	↓ lopinavir	Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly.
disulfiram/metronidazole		KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
PDE5 inhibitors: sildenafil, tadalafil, vardenafil	↑ sildenafil ↑ tadalafil ↑ vardenafil	Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. It is recommended not to exceed the following doses: Sildenafil: 25 mg every 48 hours Tadalafil: 10 mg every 72 hours Vardenafil: 2.5 mg every 72 hours
HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin	↑ atorvastatin ↑ rosuvastatin	Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with KALETRA.
Immunosuppressants: cyclosporine, tacrolimus, rapamycin	↑ immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Inhaled Steroid: fluticasone	↑ fluticasone	Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect.
Narcotic Analgesic: methadone*	↓ methadone	Dosage of methadone may need to be increased when co-administered with KALETRA.
Contraceptive: ethinyl estradiol*	↓ ethinyl estradiol	Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.

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TABLE 2. Mean (± S.D.) Pharmacokinetic Parameters for Estradiol, Estrone, and Equilin Following Coadministration of Conjugated Estrogens 0.625 mg and Progesterone Capsules 200 mg for 12 Days to Postmenopausal Women
^a Total estrogens is the sum of conjugated and unconjugated estrogen.
	Conjugated Estrogens			Conjugated Estrogens plus Progesterone Capsules
Drug	C_max (ng/mL)	T_max (hr)	AUC_(0-24h) (ng × h/mL)	C_max (ng/mL)	T_max (hr)	AUC_(0-24h) (ng × h/mL)
Estradiol	0.037 ± 0.048	12.7 ± 9.1	0.676 ± 0.737	0.030 ± 0.032	17.32 ± 1.21	0.561 ± 0.572
Estrone Total^a	3.68 ± 1.55	10.6 ± 6.8	61.3 ± 26.36	4.93 ± 2.07	7.5 ± 3.8	85.9 ± 41.2
Equilin Total^a	2.27 ± 0.95	6.0 ± 4.0	28.8 ± 13.0	3.22 ± 1.13	5.3 ± 2.6	38.1 ± 20.2

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine	Do not exceed 10 mg atorvastatin daily
Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir)	Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used.

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Interacting Agents	Prescribing Recommendations
Cyclosporine	Do not exceed 10 mg atorvastatin daily
Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir)	Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used.

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Table 2 Steady-State Plasma Concentrations of Felbamate When Coadministered With Other AEDs
AED Coadministered	AED Concentration	Felbamate Concentration
Phenytoin	↑	↓
Valproate	↑	↔**
Carbamazepine (CBZ)*CBZ epoxide	↓↑	↓
Phenobarbital	↑	↓
Not significant but an active metabolie of carbamazepine. *No significant effect.

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CYP2C19 or CYP3A4 Inducers
Clinical Impact:	Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention:	St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions (5.9)]. Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:	Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
Intervention:	Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole.

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Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio Change relative to reference)		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	Cmax	Risperidone Dose Recommendation
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Drugs That Interfere with Hemostasis
Clinical Impact:		• Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:		Monitor patients with concomitant use of VOLTAREN ^® GEL with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions ( 5.11)].
Aspirin
Clinical Impact:		Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions ( 5.2)].
Intervention:		Concomitant use of VOLTAREN ^® GEL and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions ( 5.11)]. VOLTAREN ^® GEL is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:		• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:		• During concomitant use of VOLTAREN ^® GEL and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of VOLTAREN ^® GEL and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions ( 5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter .
Diuretics
Clinical Impact:		Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:		During concomitant use of VOLTAREN ^® GEL with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see Warnings and Precautions ( 5.6)].
Digoxin
Clinical Impact:		The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:		During concomitant use of VOLTAREN ^® GEL and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:		NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:		During concomitant use of VOLTAREN ^® GEL and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:		Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:		During concomitant use of VOLTAREN ^® GEL and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:		Concomitant use of VOLTAREN ^® GEL and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention:		During concomitant use of VOLTAREN ^® GEL and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:		Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions ( 5.2)].
Intervention:		The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:		Concomitant use of VOLTAREN ^® GEL and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:		During concomitant use of VOLTAREN ^® GEL and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and Gl toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.

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Concomitant Drug Class or Food	Noted or Anticipated Outcome	Clinical Comment
HMG-Co A Reductase Inhibitors: atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin	Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality)	Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy.
Other Lipid-Lowering Drugs: fibrates, gemfibrozil
Digitalis Glycosides: digoxin	P-gp substrate; rhabdomyolysis has been reported

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AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase= Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide= Is not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Table 13. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Drugs that Affect Renal Function	A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics	Dofetilide	Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
	Sotalol	Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
	Dronedarone	Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog	Teriparatide	Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement	Thyroid	Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics	Epinephrine Norepinephrine Dopamine	Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents	Succinylcholine	May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements	Calcium	If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers		Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.

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See Table 3 for clinically significant drug interactions with celecoxib. Table 3: Clinically Significant Drug Interactions with Celecoxib EndCaption
Drugs That Interfere with Hemostasis
Clinical Impact:	Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of Celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of celecoxib with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11) ].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2) ]. In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200 to 400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100 to 325 mg).
Intervention:	Concomitant use of celecoxib and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11) ]. Celecoxib is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of celecoxib and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of celecoxib and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6) ]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of celecoxib with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6) ].
Digoxin
Clinical Impact:	The concomitant use of celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of celecoxib and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of celecoxib and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Celecoxib has no effect on methotrexate pharmacokinetics.
Intervention:	During concomitant use of celecoxib and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of celecoxib and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention:	During concomitant use of celecoxib and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2) ].
Intervention:	The concomitant use of celecoxib with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of celecoxib and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of celecoxib and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or inducers
Clinical Impact:	Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib.
Intervention:	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [see Clinical Pharmacology (12.3) ].
CYP2D6 substrates
Clinical Impact:	In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs.
Intervention:	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [see Clinical Pharmacology (12.3) ].
Corticosteroids
Clinical Impact:	Concomitant use of corticosteroids with celecoxib may increase the risk of GI ulceration or bleeding.
Intervention:	Monitor patients with concomitant use of celecoxib with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)].

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Table 7 Summary of AED Interactions with Oxcarbazepine Tablets, USP
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Tablets Dose (mg/day)	Influence of Oxcarbazepine Tablets on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400-2000	900	ncnc denotes a mean change of less than 10%	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100-150	600-1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250-500	600-1800 >1200-2400	nc ^, Pediatrics up to 40% increaseMean increase in adults at high oxcarbazepine tablets, USP doses [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400-2800	600-1800	nc	18% decrease [CI: 13% decrease, 40% decrease]

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Table 3 Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or on Predicted Interaction with INVIRASE/ritonavir
Concomitant Drug Class: Drug Name	Effect on Concentration of Saquinavir or Concomitant Drug	Clinical Comment
HIV-1 Antiviral Agents
Non-nucleoside reverse transcriptase inhibitor: DelavirdineINVIRASE/ritonavir interaction has not been evaluated.	↑ Saquinavir Effect on delavirdine is not well established	Appropriate doses of the combination with respect to safety and efficacy have not been established. Coadministration is not recommended. Liver function should be monitored frequently if this combination is prescribed.
Non-nucleoside reverse transcriptase inhibitor: EfavirenzSee Pharmacokinetics, Drug Interactions (12.3), Table 6 and Table 7 for magnitude of interactions., nevirapine	↓ Saquinavir ↔ Efavirenz	Appropriate doses of the combination of efavirenz or nevirapine and INVIRASE/ritonavir with respect to safety and efficacy have not been established. Coadministration is not recommended.
HIV-1 protease inhibitor: Indinavir	↑ Saquinavir ↑ Indinavir	Appropriate doses of the combination of indinavir and INVIRASE/ritonavir with respect to safety and efficacy have not been established. Coadministration is not recommended. Increased concentrations of indinavir may result in nephrolithiasis. For further details see complete prescribing information for Crixivan^® (indinavir).
HIV-1 protease inhibitor: Lopinavir/ritonavir (coformulated tablet)	↔ Saquinavir ↔ Lopinavir ↓ Ritonavir	Evidence from several clinical trials indicates that saquinavir concentrations achieved with the saquinavir and lopinavir/ritonavir combination are similar to those achieved following INVIRASE/ritonavir 1000/100 mg. The recommended dose for this combination is INVIRASE 1000 mg plus lopinavir/ritonavir 400/100 mg bid. Lopinavir/ritonavir in combination with INVIRASE should be used with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE [see Warnings and Precautions (5.2, 5.3)].
HIV-1 protease inhibitor: Nelfinavir	↑ Saquinavir	Combining saquinavir/ritonavir with nelfinavir is not recommended.
HIV-1 protease inhibitor: Tipranavir/ritonavir	↓ Saquinavir	Combining saquinavir with tipranavir/ritonavir is not recommended.
HIV-1 CCR5 antagonist: Maraviroc	↑ Maraviroc	Maraviroc dose should be 150 mg twice daily when coadministered with INVIRASE/ritonavir. For further details see complete prescribing information for Selzentry^® (maraviroc).
Other Agents
Ibutilide Sotalol		Additive effects on QT and/or PR interval prolongation may occur with INVIRASE/ritonavir [see Contraindications (4) and Warnings and Precautions (5.2, 5.3)]. Coadministration of INVIRASE/ritonavir and ibutilide or sotalol is not recommended.
Anticoagulant: Warfarin	↑ Warfarin	Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: Carbamazepine, phenobarbital, phenytoin	↓ Saquinavir Effect on carbamazepine, phenobarbital, and phenytoin is not well established	Saquinavir may be less effective due to decreased saquinavir plasma concentrations in patients taking these agents concomitantly. Coadministration is not recommended.
Anti-gout: Colchicine	↑ Colchicine	Treatment of gout flares-coadministration of colchicine in patients on INVIRASE/ritonavir: 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Treatment of familial Mediterranean fever (FMF) coadministration of colchicine in patients on INVIRASE/ritonavir: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Prophylaxis of gout-flares-co-administration of colchicine in patients on INVIRASE/ritonavir: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Patients with renal or hepatic impairment should not be given colchicine with INVIRASE/ritonavir.
Streptogramin antibiotics (quinupristin/dalfopristin)	Streptogramin antibiotics such as quinupristin/dalfopristin inhibit CYP3A4; saquinavir concentrations may be increased	Monitoring for saquinavir toxicity is recommended. Use with caution due to possible cardiac arrhythmias.
Fusidic acid	↑ Saquinavir ↑ Fusidic Acid ↑ Ritonavir	Concomitant use of fusidic acid and INVIRASE/ritonavir is not recommended due to potential for increased mutual toxicities. The interaction between INVIRASE/ritonavir and fusidic acid has not been formally evaluated. Co-administration of fusidic acid and INVIRASE/ritonavir can cause increased plasma concentrations of fusidic acid, saquinavir and ritonavir.
Antifungal: Ketoconazole, itraconazole	↔ Saquinavir ↔ Ritonavir ↑ Ketoconazole	When INVIRASE/ritonavir and ketoconazole are coadministered, plasma concentrations of ketoconazole are increased (see Table 6 ). Hence, doses of ketoconazole or itraconazole >200 mg/day are not recommended.
Antimycobacterial: Rifabutin	↔ Saquinavir ↑ Rifabutin ↔ Ritonavir	No dose adjustment of INVIRASE/ritonavir (1000/100 mg bid) is required if INVIRASE/ritonavir is administered in combination with rifabutin. Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse events including neutropenia and liver enzyme levels is warranted in patients receiving the combination. Consider monitoring rifabutin concentrations to ensure adequate exposure.
Antipsychotic: Quetiapine	↑ Quetiapine	Initiation of INVIRASE with ritonavir in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine drug exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking INVIRASE with ritonavir: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
Benzodiazepines : Alprazolam, clorazepate, diazepam, flurazepam	↑ Benzodiazepines	Clinical significance is unknown. Careful monitoring of patients for benzodiazepine effects is warranted; a decrease in benzodiazepine dose may be needed.
Benzodiazepine : Intravenously administered Midazolam	↑ Midazolam	If INVIRASE/ritonavir is coadministered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Calcium channel blockers : Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine	↑ Calcium channel blockers	Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid: Dexamethasone	↓ Saquinavir	INVIRASE/ritonavir may be less effective due to decreased saquinavir plasma concentrations. Coadministration is not recommended.
Digitalis Glycosides: Digoxin	↑ Digoxin Increases in serum digoxin concentration were greater in female subjects as compared to male subjects when digoxin was coadministered with INVIRASE/ritonavir.	Caution should be exercised when INVIRASE/ritonavir and digoxin are coadministered; serum digoxin concentrations should be monitored and the dose of digoxin may need to be reduced when coadministered with INVIRASE/ritonavir.
Endothelin receptor antagonists: Bosentan	↑ Bosentan	Coadministration of bosentan in patients on INVIRASE/ritonavir: In patients who have been receiving INVIRASE/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Coadministration of INVIRASE/ritonavir in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of INVIRASE/ritonavir. After at least 10 days following the initiation of INVIRASE/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Inhaled beta agonist: Salmeterol	↑ Salmeterol	Concurrent administration of salmeterol with INVIRASE/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Inhaled/nasal steroids: Fluticasone Budesonide	↑ Fluticasone	Concomitant use of fluticasone propionate and INVIRASE/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Several cases of Cushing's disease associated with this interaction have been reported in the literature. Coadministration of fluticasone propionate and INVIRASE/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. If the combination is nevertheless considered necessary, a dose reduction of fluticasone propionate with close monitoring of local and systemic effects is recommended. A switch to a corticosteroid which is not a substrate for CYP3A (e.g., beclomethasone) should be considered. In case of withdrawal of corticosteroids, progressive dose reduction may have to be performed over a longer period.
HMG-CoA reductase inhibitors : Atorvastatin	↑ Atorvastatin	Titrate atorvastatin dose carefully and use the lowest dose necessary; do not exceed atorvastatin 20 mg/day. Patients should be carefully monitored for signs and symptoms of myopathy (e.g., muscle weakness, muscle pain, rising creatine kinase).
Immunosuppressants : Cyclosporine, rapamycin	↑ Immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with INVIRASE/ritonavir.
Narcotic analgesic: Methadone	↓ Methadone	Dosage of methadone may need to be increased when coadministered with INVIRASE/ritonavir. Use with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE/ritonavir [see Contraindications (4) and Warnings and Precautions (5.2, 5.3)].
Oral contraceptives: Ethinyl estradiol	↓ Ethinyl estradiol	Alternative or additional contraceptive measures should be used when estrogen-based oral contraceptives and INVIRASE/ritonavir are coadministered.
PDE5 inhibitors (phosphodiesterase type 5 inhibitors): Sildenafil, vardenafil, tadalafil	↑ Sildenafil ↔ Saquinavir ↑ Vardenafil ↑ Tadalafil Only the combination of sildenafil with saquinavir soft gelatin capsules has been studied at doses used for treatment of erectile dysfunction.	May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Use of sildenafil (Revatio) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications (4)]. The following dose adjustments are recommended for use of tadalafil (Adcirca^®) with INVIRASE/ritonavir: Coadministration of Adcirca in patients on INVIRASE/ritonavir: In patients receiving INVIRASE/ritonavir for at least one week, start Adcirca at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Coadministration of INVIRASE/ritonavir in patients on Adcirca: Avoid use of Adcirca during the initiation of INVIRASE/ritonavir. Stop Adcirca at least 24 hours prior to starting INVIRASE/ritonavir. After at least one week following the initiation of INVIRASE/ritonavir, resume Adcirca at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: Use sildenafil with caution at reduced doses of 25 mg every 48 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir. Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir. Use tadalafil with caution at reduced doses of no more than 10 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir.
Tricyclic antidepressants : Amitriptyline, clomipramine, imipramine, maprotiline	↑ Tricyclics	Therapeutic concentration monitoring is recommended for tricyclic antidepressants when coadministered with INVIRASE/ritonavir.
Other antidepressants: Nefazodone	↑ Saquinavir	Monitoring for saquinavir toxicity is recommended.
Proton pump inhibitors: Omeprazole	↑ Saquinavir	When INVIRASE/ritonavir is co-administered with omeprazole, saquinavir concentrations are increased significantly. If omeprazole or another proton pump inhibitor is taken concomitantly with INVIRASE/ritonavir, caution is advised and monitoring for potential saquinavir toxicities is recommended, particularly gastrointestinal symptoms, increased triglycerides, deep vein thrombosis, and QT prolongation.
Herbal Products: St. John's wort (hypericum perforatum)	↓ Saquinavir	Herbal products containing St. John's wort should not be used concomitantly with INVIRASE/ritonavir because coadministration may lead to loss of virologic response and possible resistance to INVIRASE or to the class of protease inhibitors.
Other drugs that are substrates of CYP3A: Fentanyl Alfentanil	↑ Fentanyl ↑ Alfentanil	Coadministration with these drugs may accentuate the side effects reported with use of fentanyl or alfentanil including respiratory depression, apnea and bradycardia.
Vasodilators (peripheral): Intravenously administered Vincamine	↑ Vincamine	Monitoring for vincamine toxicity is recommended. Use with caution due to potential cardiac arrhythmias.
Garlic Capsules	↓ Saquinavir	Coadministration of garlic capsules and saquinavir is not recommended due to the potential for garlic capsules to induce the metabolism of saquinavir which may result in sub-therapeutic saquinavir concentrations.

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)	Do not exceed 40 mg atorvastatin daily

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion–the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide(including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide(including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄, and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5’-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.

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blood dyscrasias -
seeCONTRAINDICATIONS
cancer
collagen vascular disease
congestive heart failure

diarrhea
elevated temperature
hepatic disorders
infectious hepatitis
jaundice

hyperthyroidism
poor nutritional state
steatorrhea
vitamin K deficiency

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Drugs/Dietary Supplements That Decrease Cyclosporine Concentrations
Antibiotics nafcillin rifampin	Anticonvulsants carbamazepine oxcarbazepine phenobarbital phenytoin	Other Drugs / Dietary Supplements bosentan octreotide orlistat St. John’s Wort sulfinpyrazone terbinafine ticlopidine

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Inhibitors of CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6
Clinical Impact:	Methadone undergoes hepatic N-demethylation by several cytochrome P450 (CYP) isoforms, including CYP3A4, CYP2B6, CYP2C19, CYP2C9, and CYP2D6. The concomitant use of methadone hydrochloride tablets and CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors can increase the plasma concentration of methadone, resulting in increased or prolonged opioid effects, and may result in a fatal overdose, particularly when an inhibitor is added after a stable dose of methadone hydrochloride tablets is achieved. These effects may be more pronounced with concomitant use of drugs that inhibit more than one of the CYP enzymes listed above. After stopping a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitor, as the effects of the inhibitor decline, the methadone plasma concentration can decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or withdrawal symptoms in patients physically dependent on methadone.
Intervention:	If concomitant use is necessary, consider dosage reduction of methadone hydrochloride tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitor is discontinued, follow patients for signs of opioid withdrawal and consider increasing the methadone hydrochloride tablets dosage until stable drug effects are achieved.
Examples:	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir), fluconazole, fluvoxamine, some selective serotonin reuptake inhibitors (SSRIs) (e.g., sertraline, fluvoxamine)
Inducers of CYP3A4, CYP2B6, CYP2C19, or CYP2C9
Clinical Impact:	The concomitant use of methadone hydrochloride tablets and CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers can decrease the plasma concentration of methadone [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of withdrawal symptoms in patients physically dependent on methadone. These effects could be more pronounced with concomitant use of drugs that can induce multiple CYP enzymes. After stopping a CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducer, as the effects of the inducer decline, the methadone plasma concentration can increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression, sedation, or death.
Intervention:	If concomitant use is necessary, consider increasing the methadone hydrochloride tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducer is discontinued, consider methadone hydrochloride tablets dosage reduction and monitor for signs of respiratory depression and sedation.
Examples:	Rifampin, carbamazepine, phenytoin, St. John’s Wort, Phenobarbital
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.6)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Potentially Arrhythmogenic Agents
Clinical Impact:	Pharmacodynamic interactions may occur with concomitant use of methadone and potentially arrhythmogenic agents or drugs capable of inducing electrolyte disturbances (hypomagnesemia, hypokalemia).
Intervention:	Monitor patients closely for cardiac conduction changes.
Examples:	Drugs known to have potential to prolong QT interval: Class I and III antiarrhythmics, some neuroleptics and tricyclic antidepressants, and calcium channel blockers. Drugs capable of inducing electrolyte disturbances: Diuretics, laxatives, and, in rare cases, mineralocortocoid hormones.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions (5.8)].
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue methadone hydrochloride tablets if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.8)] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
Intervention:	The use of methadone hydrochloride tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of methadone hydrochloride tablets and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Methadone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of methadone hydrochloride tablets and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when methadone hydrochloride tablets are used concomitantly with anticholinergic drugs.

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Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2) ].
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate. [See Warnings and Precautions (5.9) .]
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.11) and Use in Specific Populations (8.5) ].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [See Adverse Reactions (6.1) .]
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions (5.16) ].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies in and postmarketing.
Sildenafil	Use with caution Two-fold increase in exposure	Monitor for sildenafil toxicity (see Clinical Pharmacology (12.3 )].
Duloxetine	Avoid Use Five-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx^®(didanosine) chewable/ buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2.4)] .	Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C Protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Figure 1: Effect of interacting drugs on the pharmacokinetics of venlafaxine and active metabolite O-desmethylvenlafaxine (ODV).

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I. Due to the competition of salicylate with other drugs for binding to serum albumin the following drug interactions may occur:
DRUG	DESCRIPTION OF INTERACTION
Sulfonylureas	Hypoglycemia potentiated.
Methotrexate	Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants	Increased bleeding.
II. Drugs changing salicylate levels by altering renal tubular reabsorption:
DRUG	DESCRIPTION OF INTERACTION
Corticosteroids	Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents	Increases plasma salicylate levels.
Alkanizing Agents	Decreased plasma salicylate levels.
III. Drugs with complicated interactions with salicylates:
DRUG	DESCRIPTION OF INTERACTION
Heparin	Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients.
Pyrazinamide	Inhibits pyrazinamide-induced hyperuricemia.
Uricosuric Agents	Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.
The following alterations of laboratory tests have been reported during salicylate therapy:
LABORATORY TESTS	EFFECT OF SALICYLATES
Thyroid Function	Decreased PBI; increased t₃ uptake.
Urinary Sugar	False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.).
5-Hydroxyindole acetic acid	False negative with fluorometric test.
Acetone ketone bodies	False positive FeCI₃ in Gerhardt reaction; red color persists with boiling.
17-OH corticosteroids	False reduced values with >4.8g q.d. salicylate.
Vanilmandelic acid	False reduced values.
Uric Acid	May increase or decrease depending on dose.
Prothrombin	Decreased levels; slightly increased prothrombin time.

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Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)	VIAGRA 50 mg (95% CI)
Supine	9.08 (5.48, 12.68)
Standing	11.62 (7.34, 15.90)

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Drugs That Interfere with Hemostasis
Clinical Impact:	• Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	• During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

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Table 3. Clinically Significant Drug Interactions Involving Drugs that Affect Cabozantinib
Strong CYP3A4 Inhibitors
Clinical Implications:	Concomitant use of CABOMETYX with a strong CYP3A4 inhibitor increased the exposure of cabozantinib compared to the use of CABOMETYX alone [see Clinical Pharmacology (12.3)]. Increased cabozantinib exposure may increase the risk of exposure-related toxicity.
Prevention or Management:	Reduce the dosage of CABOMETYX if concomitant use with strong CYP3A4 inhibitors cannot be avoided [see Dosage and Administration (2.2)].
Examples:	Boceprevir, clarithromycin, conivaptan, grapefruit juiceThe effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation dependent. Studies have shown that it can be classified as a "strong CYP3A inhibitor" when a certain preparation was used (e.g., high dose, double strength) or as a "moderate CYP3A inhibitor" when another preparation was used (e.g., low dose, single strength)., indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, and voriconazole
Strong CYP3A4 Inducers
Clinical Implications:	Concomitant use of CABOMETYX with a strong CYP3A4 inducer decreased the exposure of cabozantinib compared to the use of CABOMETYX alone [see Clinical Pharmacology (12.3)]. Decreased cabozantinib exposure may lead to reduced efficacy.
Prevention or Management:	Increase the dosage of CABOMETYX if concomitant use with strong CYP3A4 inducers cannot be avoided [see Dosage and Administration (2.2)].
Examples:	Rifampin, phenytoin, carbamazepine, phenobarbital, rifabutin, rifapentine, and St. John’s WortThe effect of St. John’s Wort varies widely and is preparation-dependent

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 7.8, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 Inhibitors, (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with VYTORIN
Verapamil, diltiazem, dronedarone	Do not exceed 10/10 mg VYTORIN daily
Amiodarone, amlodipine, ranolazine	Do not exceed 10/20 mg VYTORIN daily
Lomitapide	For patients with HoFH, do not exceed 10/20 mg VYTORIN daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 10/40 mg VYTORIN when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Table 5. Established and Other Potentially Significant Drug Interactions
↓= Decreased (induces lamotrigine glucuronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓levonorgestrel	Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and Carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Table 7 Summary of AED Interactions with Oxcarbazepine Tablets
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Tablets Dose (mg/day)	Influence of Oxcarbazepine Tablets on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400-2000	900	nc nc denotes a mean change of less than 10%	40% decrease [CI:17% decrease, 57% decrease]
Phenobarbital	100-150	600-1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI:12% decrease, 51% decrease]
Phenytoin	250-500	600-1800	nc ^, Pediatrics	30% decrease
		>1200-2400	up to 40% increase [CI: 12% increase, 60% increase] Mean increase in adults at high oxcarbazepine tablets doses	[CI: 3% decrease, 48% decrease]
Valproic acid	400-2800	600-1800	nc	18% decrease [CI:13% decrease, 40% decrease]

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Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
* Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9-Hydroxy- Risperidone Ratio*)		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	C_max	Risperidone Dose Recommendation
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Interacting Drug	Interaction
Multivalent cation- containing products including: antacids, sucralfate, multivitamins	Decreased moxifloxacin hydrochloride absorption. Take moxifloxacin hydrochloride tablet at least 4 hours before or 8 hours after these products. ( 2.2, 7.1, 12.3)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time/INR, and bleeding. ( 6, 7.2, 12.3)
Class IA and Class III antiarrhythmics:	Proarrhythmic effect may be enhanced. Avoid concomitant use. ( 5.6, 7.5)
Antidiabetic agents	Carefully monitor blood glucose. ( 5.11, 7.3)

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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Antibiotics	Antineoplastics	Anti-inflammatory Drugs	Gastrointestinal Agents
ciprofloxacin	melphalan	azapropazon	cimetidine
gentamicin		colchicine	ranitidine
tobramycin	Antifungals	diclofenac
vancomycin	amphotericin B	naproxen	Immunosuppressives
trimethoprim with sulfamethoxazole	ketoconazole	sulindac	tacrolimus

			Other Drugs
			fibric acid derivatives (e.g.,bezafibrate, fenofibrate)
			methotrexate

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir )	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)	Do not exceed 40 mg atorvastatin daily

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Figure 2: Effect of venlafaxine on the pharmacokinetics interacting drugs and their active metabolites.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Table 13: Clinically Important Drug Interactions with INVEGA SUSTENNA^®
Drugs with Potential for Inducing Orthostatic Hypotension
Clinical Impact	Because INVEGA SUSTENNA^® has the potential for inducing orthostatic hypotension, an additive effect may occur when INVEGA SUSTENNA^® is administered with other therapeutic agents that have this potential [see Warning and Precautions (5.7)]
Intervention	Monitor orthostatic vital signs in patients who are vulnerable to hypotension [see Warnings and Precautions (5.7)]
Examples	Nitrates Antihypertensive medicines: thiazide diuretics (e.g. hydrochlorothiazide); beta blockers (e.g. acebutolol); angiotensin-converting enzyme (ACE) inhibitors (e.g. lisinopril); angiotensin II receptor blockers (ARBs) (e.g. candesartan); calcium channel blockers (e.g. amlodipine); alpha-blockers (e.g. prazosin), alpha-agonists (e.g. clonidine), other diuretics (e.g. loop, K-sparing), vasodilators (e.g. hydralazine)
Strong Inducers of CYP3A4 and P-gp
Clinical Impact	The concomitant use of paliperidone and strong inducers of CYP3A4 and P-gp may decrease the exposure of paliperidone [see Clinical Pharmacology (12.3)]
Intervention	Avoid using CYP3A4 and/or P-gp inducers with INVEGA SUSTENNA^® during the 1-month dosing interval, if possible. If administering a strong inducer is necessary, consider managing the patient using paliperidone extended release tablets [see Dosage and Administration (2.5)]
Examples	Carbamazepine, rifampin, St John's Wort
Dopamine Agonist
Clinical Impact	Paliperidone may antagonize the effect of levodopa and other dopamine agonist
Intervention	Monitor and manage patient as clinically appropriate
Examples	Levodopa, bromocriptine, ropinirole and pramipexole

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Table 6. Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (C_max and AUCτ after 200 mg q12h)	Recommendations for Voriconazole Dosage Adjustment/Comments
Rifampin* and Rifabutin* (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (400 mg q 24h) (CYP450 Induction) Efavirenz (300 mg q 24h) (CYP450 Induction)	Significantly Reduced Slight decrease in AUC_t	Contraindicated When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)** (CYP450 Induction)	Significantly Reduced	Contraindicated
Low-dose Ritonavir (100 mg q12h)** (CYP450 Induction)	Reduced	Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Phenytoin* (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John’s Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives** containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole** (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIs*** (CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to voriconazole
	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Careful assessment of voriconazole effectiveness

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Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and Ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [ see Contraindications ( 4.2) ]
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of Ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate. [See Warnings and Precautions ( 5.6).]
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions ( 5.10) and Use in Specific Populations ( 8.5)].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when Ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when Ciprofloxacin is co-administered with oral antidiabetic drugs. [See Adverse Reactions ( 6.1).]
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon Ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of Ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when Ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of Ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of Ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant Ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with Ciprofloxacin [see Warnings and Precautions ( 5.15)].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with Ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution Two-fold increase in exposure	Monitor for sildenafil toxicity ( see Pharmacokinetics 12.3 ).
Duloxetine	Avoid Use Five-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity.
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration. ( 2)].	Decrease Ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid	Use with caution (interferes with renal tubular secretion of Ciprofloxacin and increases Ciprofloxacin serum levels)	Potentiation of Ciprofloxacin toxicity may occur.

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Interaction Drug	Interaction
Rifabutin, phenytoin, efavirenz, cimetidine, esomeprazoleThe drug interactions with esomeprazole and metoclopramide do not apply to posaconazole tablets.	Avoid coadministration unless the benefit outweighs the risks (7.6, 7.7, 7.8, 7.9)
Other drugs metabolized by CYP3A4	Consider dosage adjustment and monitor for adverse effects and toxicity (7.1, 7.10, 7.11)
Digoxin	Monitor digoxin plasma concentrations (7.12)
Fosamprenavir, metoclopramide	Monitor for breakthrough fungal infections (7.6, 7.13)

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine concentrations approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine and carbamazepine epoxide	? carbamazepine epoxide	May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2 fold.
Valproate	? valproate	There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Table 5 Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours in healthy adult subjects (n=24)
Concomitant Drug	C_maxSS (Peak plasma concentration)	AUCss_(0-12h) (Extent of systemic exposure)
Erythromycin (500 mg every 8 hrs)	+82%	+109%
Ketoconazole (400 mg once daily)	+135%	+164%

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Table 3. Drugs That May Alter T4 and Triiodothyronine (T3) Serum Transport Without Affecting Free Thyroxine (FT4) Concentration (Euthyroidism)
Drug or Drug Class	Effect
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	These drugs may increase serum thyroxine-binding globulin (TBG) concentration.
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid	These drugs may decrease serum TBG concentration.
Potential impact (below): Administration of these agents with SYNTHROID results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations.
Salicylates (> 2 g/day)	Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total T4 levels may decrease by as much as 30%.
Other drugs: Carbamazepine Furosemide (> 80 mg IV) Heparin Hydantoins Non-Steroidal Anti-inflammatory Drugs - Fenamates	These drugs may cause protein-binding site displacement. Furosemide has been shown to inhibit the protein binding of T4 to TBG and albumin, causing an increase free T4 fraction in serum. Furosemide competes for T4-binding sites on TBG, prealbumin, and albumin, so that a single high dose can acutely lower the total T4 level. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total and free T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. Closely monitor thyroid hormone parameters.

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Table 3: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Indinavir (See PRECAUTIONS, Table 9 for Recommended Alterations in Dose or Regimen)
Coadministered drug	Dose of Coadministered drug (mg)	Dose of CRIXIVAN (mg)	n	Ratio (with/without CRIXIVAN) of Coadministered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00
				C_max	AUC	C_min
All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
Clarithromycin	500 twice daily, 7 days	800 three times daily, 7 days	12	1.19 (1.02, 1.39)	1.47 (1.30, 1.65)	1.97 (1.58, 2.46) n=11
Efavirenz	200 once daily, 14 days	800 three times daily, 14 days	20	No significant change	No significant change	--
Ethinyl Estradiol (ORTHO-NOVUM 1/35)Registered trademark of Ortho Pharmaceutical Corporation	35 mcg, 8 days	800 three times daily, 8 days	18	1.02 (0.96, 1.09)	1.22 (1.15, 1.30)	1.37 (1.24, 1.51)
Isoniazid	300 once daily in the morning, 8 days	800 three times daily, 8 days	11	1.34 (1.12, 1.60)	1.12 (1.03, 1.22)	1.00 (0.92, 1.08)
MethadoneStudy conducted in subjects on methadone maintenance.	20-60 once daily in the morning, 8 days	800 three times daily, 8 days	12	0.93 (0.84, 1.03)	0.96 (0.86, 1.06)	1.06 (0.94, 1.19)
Norethindrone (ORTHO-NOVUM 1/35)	1 mcg, 8 days	800 three times daily, 8 days	18	1.05 (0.95, 1.16)	1.26 (1.20, 1.31)	1.44 (1.32, 1.57)
Rifabutin ^•150 mg once daily in the morning, 11 days + indinavir compared to 300 mg once daily in the morning, 11 days alone	150 once daily in the morning, 10 days 300 once daily in the morning, 10 days	800 three times daily, 10 days 800 three times daily, 10 days	14 10	1.29 (1.05, 1.59) 2.34 (1.64, 3.35)	1.54 (1.33, 1.79) 2.73 (1.99, 3.77)	1.99 (1.71, 2.31) n=13 3.44 (2.65, 4.46) n=9
Ritonavir	100 twice daily, 14 days	800 twice daily, 14 days	10, 4Parallel group design; n for coadministered drug + indinavir, n for coadministered drug alone.	1.61 (1.13, 2.29)	1.72 (1.20, 2.48)	1.62 (0.93, 2.85)
	200 twice daily, 14 days	800 twice daily, 14 days	9, 5	1.19 (0.85, 1.66)	1.96 (1.39, 2.76)	4.71 (2.66, 8.33) n=9, 4
Saquinavir
Hard gel formulation	600 single dose	800 three times daily, 2 days	6	4.7 (2.7, 8.1)	6.0 (4.0, 9.1)	2.9 (1.7, 4.7)C_6hr
Soft gel formulation	800 single dose	800 three times daily, 2 days	6	6.5 (4.7, 9.1)	7.2 (4.3, 11.9)	5.5 (2.2, 14.1)
Soft gel formulation	1200 single dose	800 three times daily, 2 days	6	4.0 (2.7, 5.9)	4.6 (3.2, 6.7)	5.5 (3.7, 8.3)
Sildenafil	25 single dose	800 three times daily	6	See text below for discussion of interaction.
StavudineStudy conducted in HIV-positive subjects.	40 twice daily, 7 days	800 three times daily, 7 days	13	0.86 (0.73, 1.03)	1.21 (1.09, 1.33)	Not Done
Theophylline	250 single dose (on Days 1 and 7)	800 three times daily, 6 days (Days 2 to 7)	12, 4	0.88 (0.76, 1.03)	1.14 (1.04, 1.24)	1.13 (0.86, 1.49) n=7, 3
Trimethoprim/ Sulfamethoxazole
Trimethoprim	800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days	400 q6h, 7 days	12	1.18 (1.05, 1.32)	1.18 (1.05, 1.33)	1.18 (1.00, 1.39)
Trimethoprim/ Sulfamethoxazole
Sulfamethoxazole	800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days	400 q6h, 7 days	12	1.01 (0.95, 1.08)	1.05 (1.01, 1.09)	1.05 (0.97, 1.14)
Vardenafil	10 single dose	800 three times daily	18	See text below for discussion of interaction.
Zidovudine	200 three times daily, 7 days	1000 three times daily, 7 days	12	0.89 (0.73, 1.09)	1.17 (1.07, 1.29)	1.51 (0.71, 3.20) n=4
Zidovudine/ Lamivudine
Zidovudine	200/150 three times daily, 7 days	800 three times daily, 7 days	6, 7	1.23 (0.74, 2.03)	1.39 (1.02, 1.89)	1.08 (0.77, 1.50) n=5, 5
Zidovudine/ Lamivudine
Lamivudine	200/150 three times daily, 7 days	800 three times daily, 7 days	6, 7	0.73 (0.52, 1.02)	0.91 (0.66, 1.26)	0.88 (0.59, 1.33)

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Table 25: Clinically Important Drug Interactions with ABILIFY:
Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of ABILIFY with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of ABILIFY alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of ABILIFY with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the ABILIFY dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of ABILIFY and carbamazepine decreased the exposure of aripiprazole compared to the use of ABILIFY alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of ABILIFY with a strong CYP3A4 inducer, consider increasing the ABILIFY dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.7)].
Benzodiazepines (e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.7)]	Monitor sedation and blood pressure. Adjust dose accordingly.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄ . Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³ I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 3 Includes clinically significant drug interactions with buprenorphine and naloxone sublingual tablets
Benzodiazepines
Clinical Impact:	There have been a number of reports regarding coma and death associated with the misuse and abuse of the combination of buprenorphine and benzodiazepines. In many, but not all of these cases, buprenorphine was misused by self-injection of crushed buprenorphine tablets. Preclinical studies have shown that the combination of benzodiazepines and buprenorphine altered the usual ceiling effect on buprenorphine-induced respiratory depression, making the respiratory effects of buprenorphine appear similar to those of full opioid agonists.
Intervention:	Closely monitor patients with concurrent use of Buprenorphine and Naloxone Sublingual Tablets and benzodiazepines. Warn patients that it is extremely dangerous to self-administer benzodiazepines while taking Buprenorphine and Naloxone Sublingual Tablets, and warn patients to use benzodiazepines concurrently with Buprenorphine and Naloxone Sublingual Tablets only as directed by their healthcare provider.
Non-Benzodiazepine Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effects, the concomitant use of non-benzodiazepine CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.2, 5.3)].
Examples:	Alcohol, non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids.
Inhibitors of CYP3A4
Clinical Impact:	The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of Buprenorphine and Naloxone Sublingual Tablets is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease [see Clinical Pharmacology (12.3)], potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to buprenorphine.
Intervention:	If concomitant use is necessary, consider dosage reduction of Buprenorphine and Naloxone Sublingual Tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the Buprenorphine and Naloxone Sublingual Tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples:	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact:	The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine [see Clinical Pharmacology (12.3)], potentially resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both therapeutic effects and adverse reactions and may cause serious respiratory depression.
Intervention:	If concomitant use is necessary, consider increasing the Buprenorphine and Naloxone Sublingual Tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider Buprenorphine and Naloxone Sublingual Tablets dosage reduction and monitor for signs of respiratory depression.
Examples:	Rifampin, carbamazepine, phenytoin
Antiretrovirals: Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Clinical Impact:	Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine, and etravirine are known CYP3A inducers, whereas delaviridine is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects.
Intervention:	Patients who are on chronic Buprenorphine and Naloxone Sublingual Tablets treatment should have their dose monitored if NNRTIs are added to their treatment regimen.
Examples:	efavirenz, nevirapine, etravirine, delavirdine
Antiretrovirals: Protease inhibitors (PIs)
Clinical Impact:	Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity (atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine, and patients in one study reported increased sedation. Symptoms of opioid excess have been found in post-marketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly.
Intervention:	Monitor patients taking Buprenorphine and Naloxone Sublingual Tablets and atazanavir with and without ritonavir, and reduce dose of Buprenorphine and Naloxone Sublingual Tablets if warranted.
Examples:	atazanavir, ritonavir
Antiretrovirals: Nucleoside reverse transcriptase inhibitors (NRTIs)
Clinical Impact:	Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected.
Intervention:	None
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Buprenorphine and Naloxone Sublingual Tablets if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).
Intervention:	The use of Buprenorphine and Naloxone Sublingual Tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Muscle Relaxants
Clinical Impact:	Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients receiving muscle relaxants and Buprenorphine and Naloxone Sublingual Tablets for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Buprenorphine and Naloxone Sublingual Tablets and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when Buprenorphine and Naloxone Sublingual Tablets are used concomitantly with anticholinergic drugs.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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NA = Not available/reported
Digoxin concentrations increased greater than 50%
	Digoxin Serum Concentration Increase	Digoxin AUC Increase	Recommendations
Amiodarone	70%	NA	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
Captopril	58%	39%
Clarithromycin	NA	70%
Dronedarone	NA	150%
Gentamicin	129-212%	NA
Erythromycin	100%	NA
Itraconazole	80%	NA
Lapatinib	NA	180%
Nitrendipine	57%	15%
Propafenone	NA	60-270%
Quinidine	100%	NA
Ranolazine	50%	NA
Ritonavir	NA	86%
Telaprevir	50%	85%
Tetracycline	100%	NA
Verapamil	50-75%	NA
Digoxin concentrations increased less than 50%
Atorvastatin	22%	15%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
Carvedilol	16%	14%
Conivaptan	33%	43%
Diltiazem	20%	NA
Indomethacin	40%	NA
Nefazodone	27%	15%
Nifedipine	45%	NA
Propantheline	24%	24%
Quinine	NA	33%
Rabeprazole	29%	19%
Saquinavir	27%	49%
Spironolactone	25%	NA
Telmisartan	20-49%	NA
Ticagrelor	31%	28%
Tolvaptan	30%	20%
Trimethoprim	22-28%	NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate and sulfasalazine			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20-40% as necessary.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistatcontaining products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Table 7: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (C_max and AUC_τ after 200 mg q12h)	Recommendations for Voriconazole Dosage Adjustment/Comments
RifampinResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects and Rifabutin (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (400 mg q24h)Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (300 mg q24h) (CYP450 Induction)	Slight Decrease in AUC _τ	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h) (CYP450 Induction)	Significantly Reduced	Contraindicated
Low-dose Ritonavir (100 mg q12h) (CYP450 Induction)	Reduced	Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Phenytoin (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John's Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir

	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to voriconazole

	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Careful assessment of voriconazole effectiveness

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Drugs That Interfere with Hemostasis
Clinical Impact:	Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of indomethacin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions ( 5.11 )].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions ( 5.2 ) ].
Intervention:	Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions ( 5.11 )].Indomethacin is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of indomethacin capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.During concomitant use of indomethacin capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions ( 5.6 )].When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.It has been reported that the addition of triamterene to a maintenance schedule of Indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together.Both indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently [ see Warnings and Precautions ( 5.6 )].
Intervention:	Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels. [ see Warnings and Precautions ( 5.6 )].
Digoxin
Clinical Impact:	The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention:	During concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions ( 5.2 )]. Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin [see Clinical Pharmacology ( 12.3 )].In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage.
Intervention:	The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Probenecid
Clinical Impact:	When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased.
Intervention:	During the concomitant use of indomethacin and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments.

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Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours in healthy adult subjects (n=24)
Concomitant Drug	C_maxSS (Peak plasma concentration)	AUC_ss(0–12h) (Extent of systemic exposure)
Erythromycin (500 mg every 8 hrs)	+82%	+109%

Ketoconazole (400 mg once daily)	+135%	+164%

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Inhibitors of CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6
Clinical Impact:	Methadone undergoes hepatic N-demethylation by several cytochrome P450 (CYP) isoforms, including CYP3A4, CYP2B6, CYP2C19, CYP2C9, and CYP2D6. The concomitant use of methadone hydrochloride tablets and CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors can increase the plasma concentration of methadone, resulting in increased or prolonged opioid effects, and may result in a fatal overdose, particularly when an inhibitor is added after a stable dose of methadone hydrochloride tablets is achieved. These effects may be more pronounced with concomitant use of drugs that inhibit more than one of the CYP enzymes listed above. After stopping a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitor, as the effects of the inhibitor decline, the methadone plasma concentration can decrease [see Clinical Pharmacology (12.3) ], resulting in decreased opioid efficacy or withdrawal symptoms in patients physically dependent on methadone.
Intervention:	If concomitant use is necessary, consider dosage reduction of methadone hydrochloride tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitor is discontinued, follow patients for signs of opioid withdrawal and consider increasing the methadone hydrochloride tablets dosage until stable drug effects are achieved.
Examples	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir), fluconazole, fluvoxamine, Some selective serotonin reuptake inhibitors (SSRIs) (e.g., sertraline, fluvoxamine)
Inducers of CYP3A4, CYP2B6, CYP2C19, or CYP2C9
Clinical Impact:	The concomitant use of methadone hydrochloride tablets and CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers can decrease the plasma concentration of methadone [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of withdrawal symptomsin patients physically dependent on methadone. These effects could be more pronouncedwith concomitant use of drugs that can induce multiple CYP enzymes.After stopping a CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducer, as the effects ofthe inducer decline, the methadone plasma concentration can increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects andadverse reactions, and may cause serious respiratory depression, sedation, or death.
Intervention:	If concomitant use is necessary, consider increasing the methadone hydrochloride tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducer is discontinued, consider methadone hydrochloride tablets dosage reduction and monitor for signs of respiratory depression and sedation.
Examples:	Rifampin, carbamazepine, phenytoin, St. John’s Wort, Phenobarbital
Benzodiazepines and other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.6) ].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Potentially Arrhythmogenic Agents
Clinical Impact:	Pharmacodynamic interactions may occur with concomitant use of methadone and potentially arrhythmogenic agents or drugs capable of inducing electrolyte disturbances (hypomagnesemia, hypokalemia).
Intervention:	Monitor patients closely for cardiac conduction changes.
Examples:	Drugs known to have potential to prolong QT interval: Class I and III antiarrhythmics, some neuroleptics and tricyclic antidepressants, and calcium channel blockers. Drugs capable of inducing electrolyte disturbances: Diuretics, laxatives, and, in rare cases, mineralocortocoid hormones.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions (5.8) ].
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue methadone hydrochloride tablets if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.8)] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
Intervention:	The use of methadone hydrochloride tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of methadone hydrochloride tablets and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Methadone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of methadone hydrochloride tablets and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when Methadone hydrochloride tablets are used concomitantly with anticholinergic drugs.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Inhibitors of CYP3A4
Clinical Impact:	The concomitant use of OTFC and CYP3A4 inhibitors can increase the plasma concentration of fentanyl, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of OTFC is achieved [se e Warnings and Precautions ( 5.3 )]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl plasma concentration will decrease [ see Clinical Pharmacology ( 12.3 )], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to fentanyl.
Intervention:	If concomitant use is necessary, consider dosage reduction of OTFC until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the OTFC dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples:	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir), grapefruit juice.
CYP3A4 Inducers
Clinical Impact:	The concomitant use of OTFC and CYP3A4 inducers can decrease the plasma concentration of fentanyl [ see Clinical Pharmacology ( 12.3 )], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to fentanyl [ see Warnings and Precautions ( 5.3 )]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase [ see Clinical Pharmacology ( 12.3 )], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention:	If concomitant use is necessary, consider increasing the OTFC dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider OTFC dosage reduction and monitor for signs of respiratory depression.
Examples:	Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions ( 5.4 )].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions ( 5.10 )].
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue OTFC if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome [se e Warnings and Precautions ( 5.10 )] or opioid toxicity (e.g., respiratory depression, coma) [ see Warnings and Precautions ( 5.1 )].
Intervention:	The use of OTFC is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	Phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of OTFC and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	Butorphanol, nalbuphine, pentazocine, buprenorphrine
Muscle Relaxants
Clinical Impact:	Fentanyl may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of OTFC and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when OTFC is used concomitantly with anticholinergic drugs.

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^a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
^b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated.

AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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AED Co - administered	AED Concentration	Topiramate Concentration
Phenytoin	NCor25%increase ^a	48%decrease
Carbamazepine(CBZ)	NC	40%decrease
CBZepoxide ^b	NC	NE
Valproic acid	11%decrease	14%decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NCatTPM dosesupto400 mg/day	13%decrease

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Table 7. Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C_max and AUC _τ)	Recommendations for Drug Dosage Adjustment/Comments
SirolimusResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (400 mg q24h)Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects (CYP3A4 Inhibition) Efavirenz (300 mg q24h) (CYP3A4 Inhibition)	Significantly Increased Slight Increase in AUC_τ	Contraindicated When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High dose Ritonavir (400 mg q12h)(CYP3A4 Inhibition)	No Significant Effect of Voriconazole on Ritonavir C_max or AUC_τ	Contraindicated because of significant reduction of voriconazole C_max and AUC_τ
Low dose Ritonavir (100 mg q12h)	Slight Decrease in Ritonavir C_max and AUC_τ	Coadministration of voriconazole and low dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole C_max and AUC_τ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of Torsades de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated
Cyclosporine (CYP3A4 Inhibition)	AUC_τ Significantly Increased; No Significant Effect on C_max	When initiating therapy with voriconazole in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
MethadoneResults based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30 mg to 100 mg q24h) (CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed.
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7)].
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see Drug Interactions (7)].
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7)].
NSAIDsNon-Steroidal Anti-Inflammatory Drug including, ibuprofen and diclofenac (CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [see Drug Interactions (7)].
Tacrolimus (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with voriconazole in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)	Increased	Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with voriconazole in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects on Indinavir Exposure	No dosage adjustment for indinavir when coadministered with voriconazole
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.
Everolimus (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Concomitant administration of voriconazole and everolimus is not recommended.

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Drugs That Interfere with Hemostasis
Clinical Impact:	• Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	• During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level. (5.9, 7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding. (7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose. (7)
Phenytoin	Monitor phenytoin level (7)
Methotrexate	Monitor for methotrexate toxicity (7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine. (7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased CIPRO absorption. Take 2 hours before or 6 hours after CIPRO (2.2, 7)

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Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.8)].
Benzodiazepines (e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.8)]	Monitor sedation and blood pressure. Adjust dose accordingly.

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Table 3Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Table 5: Drugs having clinically important interactions with amphetamines.
MAO Inhibitors (MAOI)
Clinical Impact	MAOI antidepressants slow amphetamine metabolism, increasing amphetamines effect on the release of norepinephrine and other monoamines from adrenergic nerve endings causing headaches and other signs of hypertensive crisis. Toxic neurological effects and malignant hyperpyrexia can occur, sometimes with fatal results.
Intervention	Do not administer ADZENYS XR-ODT during or within 14 days following the administration of MAOI [see Contraindications (4) ].
Examples	selegiline, isocarboxazid, phenelzine, tranylcypromine
Serotonergic Drugs
Clinical Impact	The concomitant use of ADZENYS XR-ODT and serotonergic drugs increases the risk of serotonin syndrome.
Intervention	Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome, particularly during ADZENYS XR-ODT initiation or dosage increase. If serotonin syndrome occurs, discontinue ADZENYS XR-ODT and the concomitant serotonergic drug(s) [see Warnings and Precautions (5.7)].
Examples	selective serotonin reuptake inhibitors (SSRI), serotonin norepinephrine reuptake inhibitors (SNRI), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John's Wort
Alkalinizing Agents
Clinical Impact	Increase blood levels and potentiate the action of amphetamine.
Intervention	Co-administration of ADZENYS XR-ODT and gastrointestinal alkalinizing agents should be avoided.
Examples	Gastrointestinal alkalinizing agents (e.g., sodium bicarbonate). Urinary alkalinizing agents (e.g., acetazolamide, some thiazides).
Acidifying Agents
Clinical Impact	Lower blood levels and efficacy of amphetamines.
Intervention	Increase dose based on clinical response.
Examples	Gastrointestinal acidifying agents (e.g., guanethidine, reserpine, glutamic acid HCl, ascorbic acid).
Tricyclic Antidepressants
Clinical Impact	May enhance the activity of tricyclic or sympathomimetic agents causing striking and sustained increases in the concentration of d-amphetamine in the brain; cardiovascular effects can be potentiated.
Intervention	Monitor frequently and adjust or use alternative therapy based on clinical response.
Examples	desipramine, protriptyline

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Drugs That May Potentiate Renal Dysfunction
Antibiotics	Antineoplastics	Anti-Inflammatory Drugs	Gastrointestinal Agents
ciprofloxacin	melphalan	azapropazon	cimetidine
gentamicin		colchicine	ranitidine
tobramycin	Antifungals	diclofenac
trimethoprim	amphotericin B	naproxen	Immunosuppressives
with	ketoconazole	sulindac	tacrolimus
sulfamethoxazole
vancomycin			Other Drugs
			fibric acid derivatives
			(e.g., bezafibrate,
			fenofibrate)
			methotrexate

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Table II. Clinically significant drug interactions with theophylline.Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
Drug	Type of Interaction	EffectAverage effect on steady-state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine	Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.
Alcohol	A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours.	30% increase
Allopurinol	Decreases theophylline clearance at allopurinol doses ≥600 mg/day.	25% increase
Aminoglutethimide	Increases theophylline clearance by induction of microsomal enzyme activity.	25% decrease
Carbamazepine	Similar to aminoglutethimide.	30% decrease
Cimetidine	Decreases theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase
Ciprofloxacin	Similar to cimetidine.	40% increase
Clarithromycin	Similar to erythromycin.	25% increase
Diazepam	Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.	Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram	Decreases theophylline clearance by inhibiting hydroxylation and demethylation.	50% increase
Enoxacin	Similar to cimetidine.	300% increase
Ephedrine	Synergistic CNS effects	Increased frequency of nausea, nervousness, and insomnia.
Erythromycin	Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen	Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.	30% increase
Flurazepam	Similar to diazepam.	Similar to diazepam.
Fluvoxamine	Similar to cimetidine.	Similar to cimetidine.
Halothane	Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.	Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A	Decreases theophylline clearance.	100% increase
Isoproterenol (IV)	Increase theophylline clearance.	20% increase
Ketamine	Pharmacologic	May lower theophylline seizure threshold.
Lithium	Theophylline increases renal lithium clearance.	Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam	Similar to diazepam.	Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.	20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine	Similar to disulfiram.	80% increase
Midazolam	Similar to diazepam.	Similar to diazepam.
Moricizine	Increases theophylline clearance.	25% decrease
Pancuronium	Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.	Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline	Decreases theophylline clearance.	30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.	25% decrease after two weeks of concurrent PB.
Phenytoin	Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.	Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone	Decreases theophylline clearance and pharmacologic interaction.	40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and pharmacologic interaction.	100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin	Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.	20 to 40% decrease
Sulfinpyrazone	Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.	20% increase
Tacrine	Similar to cimetidine, also increases renal clearance of theophylline.	90% increase
Thiabendazole	Decreases theophylline clearance.	190% increase
Ticlopidine	Decreases theophylline clearance.	60% increase
Troleandomycin	Similar to erythromycin.	33 to 100% increase depending on troleandomycin dose.
Verapamil	Similar to disulfiram.	20% increase

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

Table name:

Drug	Description
Corticosteroids	Decreases plasma salicylate level; Tapering doses of steroids may promote salicylism
Ammonium Sulfate	Increases plasma salicylate level

Table name:

Table 4: Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
Drug Name	Effect on Concentration of Nevirapine or Concomitant Drug	Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/RitonavirThe interaction between nevirapine and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.	↓ Atazanavir ↑ Nevirapine	Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir	↓ Amprenavir ↑ Nevirapine	Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir	↓ Amprenavir ↑ Nevirapine	No dosing adjustments are required when nevirapine is co-administered with 700 mg/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir	↓ Indinavir	The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir	↓ Lopinavir	Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500 mg/125 mg tablets twice daily or 533 mg/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra^® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir	↓ Nelfinavir M8 Metabolite ↓ Nelfinavir C_min	The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/Ritonavir	The interaction between nevirapine and saquinavir/ritonavir has not been evaluated.	The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz	↓ Efavirenz	The appropriate doses of these combinations with respect to safety and efficacy have not been established.
Delavirdine Etravirine Rilpivirine		Plasma concentrations may be altered. Nevirapine should not be co-administered with another NNRTI as this combination has not been shown to be beneficial.
Hepatitis C Antiviral Agents
Boceprevir	Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine.	Nevirapine and boceprevir should not be co-administered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy.
Telaprevir	Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir.	Nevirapine and telaprevir should not be co-administered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events.
Other Agents
Analgesics: Methadone	↓ Methadone	Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics: Amiodarone, disopyramide, lidocaine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Antibiotics: Clarithromycin	↓ Clarithromycin ↑ 14-OH clarithromycin	Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Rifabutin	↑ Rifabutin	Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin	↓ Nevirapine	Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants: Carbamazepine, clonazepam, ethosuximide	Plasma concentrations of nevirapine and the anticonvulsant may be decreased.	Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals: Fluconazole	↑ Nevirapine	Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Ketoconazole	↓ Ketoconazole	Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Itraconazole	↓ Itraconazole	Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics: Warfarin	Plasma concentrations may be increased.	Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers: Diltiazem, nifedipine, verapamil	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Cancer chemotherapy: Cyclophosphamide	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Ergot alkaloids: Ergotamine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Motility agents: Cisapride	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Opiate agonists: Fentanyl	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Oral contraceptives: Ethinyl estradiol and Norethindrone	↓ Ethinyl estradiol ↓ Norethindrone	Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.

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Table 23: Clinically Important Drug Interactions with Aripiprazole:
Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [ see CLINICAL PHARMACOLOGY ( 12 . 3 )].	With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [ see DOSAGE AND ADMINISTRATION ( 2 . 7 )].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [ see CLINICAL PHARMACOLOGY ( 12 . 3 )].	With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [ see DOSAGE AND ADMINISTRATION ( 2 . 7 )].
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [ see WARNINGS AND PRECAUTIONS ( 5 . 7 )].
Benzodiazepines (e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepamalone [ see WARNINGS AND PRECAUTIONS ( 5 . 7 )]	Monitor sedation and blood pressure. Adjust dose accordingly.

Table name: 250 mg (adults weighing at least 60 kg with creatinine clearance of at least 60 mL/min) 200 mg (adults weighing less than 60 kg with creatinine clearance of at least 60 mL/min)VIDEX and tenofovir disoproxil fumarate may be taken together in the fasted state. If tenofovir disoproxil fumarate is taken with food, VIDEX should be taken on an empty stomach (at least 30 minutes before food or 2 hours after food). Patients should be monitored for didanosine-associated toxicities and clinical response.

Table 8: Established Drug Interactions with VIDEX
Drug	Effect	Clinical Comment
↑ Indicates increase. ↓ Indicates decrease. ^a The dosing recommendation for coadministration of VIDEX EC and tenofovir disoproxil fumarate with respect to meal consumption differs from that of VIDEX. See the complete prescribing information for VIDEX EC.
ciprofloxacin	↓ ciprofloxacin concentration	Administer VIDEX at least 2 hours after or 6 hours before ciprofloxacin.
delavirdine	↓ delavirdine concentration	Administer VIDEX 1 hour after delavirdine.
ganciclovir	↑ didanosine concentration	If there is no suitable alternative to ganciclovir, then use in combination with VIDEX with caution. Monitor for didanosine-associated toxicity.
indinavir	↓ indinavir concentration	Administer VIDEX 1 hour after indinavir.
methadone	↓ didanosine concentration	Do not coadminister methadone with VIDEX pediatric powder due to significant decreases in didanosine concentrations. If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is VIDEX EC. Patients should be closely monitored for adequate clinical response when VIDEX EC is coadministered with methadone, including monitoring for changes in HIV RNA viral load.
nelfinavir	No interaction 1 hour after didanosine	Administer nelfinavir 1 hour after VIDEX.
tenofovir disoproxil fumarate	↑ didanosine concentration	A dose reduction of VIDEX to the following dosage once daily is recommended.^a

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion–the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide(including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide(including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄, and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5’-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.

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Table 6: Clinically Significant Drug Interactions with Paricalcitol
CYP3A Inhibitors
Clinical Impact	Paricalcitol is partially metabolized by CYP3A. Hence, exposure of paricalcitol will increase upon co-administration with strong CYP3A inhibitors such as but not limited to: boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole.
Intervention	Dose adjustment of paricalcitol capsules may be necessary. Monitor closely for iPTH and serum calcium concentrations, if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor.
Cholestyramine
Clinical Impact	Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of paricalcitol.
Intervention	Recommend to take paricalcitol capsules at least 1 hour before or 4 to 6 hours after taking cholestyramine (or at as great an interval as possible) to avoid impeding absorption of paricalcitol.
Mineral Oil
Clinical Impact	Mineral oil or other substances that may affect absorption of fat may influence the absorption of paricalcitol.
Intervention	Recommend to take paricalcitol capsules at least 1 hour before or 4 to 6 hours after taking mineral oil (or at as great an interval as possible) to avoid affecting absorption of paricalcitol.

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Table 13. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation). ↑ = Increased (inhibits lamotrigine glucuronidation). ? = Conflicting data.
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Table 14: Clinically Important Drug Interactions: Effect of other Drugs on Guanfacine Extended-Release
Concomitant Drug Name or Drug Class	Clinical Rationale and Magnitude of Drug Interaction	Clinical Recommendation
Strong and moderate CYP3A4 inhibitors, e.g., ketoconazole, fluconazole	Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in an increase in exposure	Consider dose reduction [see Dosage and administration ( 2.7 )]
Strong and moderate CYP3A4 inducers, e.g., rifampin, efavirenz	Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in a decrease in exposure	Consider dose increase [see Dosage and administration ( 2.7 )]

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AED Coadministered	AED Concentration	Topiramate Concentration
^a= Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. ^b= Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. NE = Not Evaluated
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Drug	Description
Corticosteroids	Decreases plasma salicylate level; tapering doses of steroids may promote salicylism
Ammonium Sulfate	Increases plasma salicylate level

Table name:

Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, gemfibrozil, cyclosporine,danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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Table 4 Other Potentially Significant Drug Interactions
Concomitant Drug Class or Food	Noted or anticipated Outcome	Clinical Comment
HMG-Co A Reductase Inhibitors: atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin	Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality)	Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy.
Other Lipid Lowering Drugs: fibrates, gemfibrozil
Digitalis Glycosides: digoxin	P-gp substrate; rhabdomyolysis has been reported

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Effects on Steady-State Fexofenadine Pharmacokinetics After 7 Days of Co-Administration with Fexofenadine Hydrochloride 120 mg Every 12 Hours (two times the recommended twice daily dose) in Healthy Volunteers (n=24)
Concomitant Drug	C_max SS (Peak plasma concentration)	AUC_SS(0–12h) (Extent of systemic exposure)
Erythromycin (500 mg every 8 hrs)	+82%	+109%
Ketoconazole (400 mg once daily)	+135%	+164%

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TABLE 2. Mean (± S.D.) Pharmacokinetic Parameters for Estradiol, Estrone, and Equilin Following Coadministration of Conjugated Estrogens 0.625 mg and PROMETRIUM Capsules 200 mg for 12 Days to Postmenopausal Women
^a Total estrogens is the sum of conjugated and unconjugated estrogen.
	Conjugated Estrogens			Conjugated Estrogens plus PROMETRIUM Capsules
Drug	C_max (ng/mL)	T_max (hr)	AUC_(0-24h) (ng × h/mL)	C_max (ng/mL)	T_max (hr)	AUC_(0-24h) (ng × h/mL)
Estradiol	0.037 ± 0.048	12.7 ± 9.1	0.676 ± 0.737	0.030 ± 0.032	17.32 ± 1.21	0.561 ± 0.572
Estrone Total^a	3.68 ± 1.55	10.6 ± 6.8	61.3 ± 26.36	4.93 ± 2.07	7.5 ± 3.8	85.9 ± 41.2
Equilin Total^a	2.27 ± 0.95	6.0 ± 4.0	28.8 ± 13.0	3.22 ± 1.13	5.3 ± 2.6	38.1 ± 20.2

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Table 5 Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours in healthy adult subjects (n=24)
Concomitant Drug	CmaxSS (Peak plasma concentration)	AUCss(0-12h) (Extent of systemic exposure)
Erythromycin (500 mg every 8 hrs)	+82%	+109%
Ketoconazole (400 mg once daily)	+135%	+164%

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Interacting Drug	Interaction
Multivalent cation-containing products including: antacids, sucralfate, multivitamins	Decreased moxifloxacin absorption. Take moxifloxacin hydrochloride tablet at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time/INR, and bleeding. (6, 7.2, 12.3)
Class IA and Class III antiarrhythmics:	Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.6, 7.5)
Antidiabetic agents	Carefully monitor blood glucose. (5.11, 7.3)

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Concomitant Drug Name	Effect of Carbamazepine on Other Drugs	Clinical Recommendation
Lithium	May increase the risk of neurotoxic side effects	Use with intensive monitoring
Isoniazid	May increase isoniazid-induced hepatotoxicity
Diuretics (e.g., hydrochlorothiazide, furosemide)	May lead to symptomatic hyponatremia
Hormonal contraceptives (e.g., oral and levonorgestrel subdermal implant contraceptives)	May render the contraceptives less effective because the plasma concentrations of the hormones may be decreased; breakthrough bleeding and unintended pregnancies have been reported	Consider alternative or back-up methods of contraception
Neuromuscular blocking agents (e.g., pancuronium, vecuronium, rocuronium, and cisatracurium)	Resistance to the neuromuscular blocking action of the non-depolarizing neuromuscular blocking agents	Closely monitor patients for more rapid recovery from neuromuscular blockade than expected; infusion rate may need to be higher
Delavirdine or other non-nucleoside reverse transcriptase inhibitors (NNRTIs)	Decrease in delavirdine or NNRTI levels	Contraindicated with carbamazepine

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Table 6 Clinically Important Drug Interactions
Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Tricyclic antidepressants	Increase blood pressure and may counteract clonidine’s hypotensive effects	Monitor blood pressure and adjust as needed
Antihypertensive drugs	Potentiate clonidine’s hypotensive effects	Monitor blood pressure and adjust as needed
CNS depressants	Potentiate sedating effects	Avoid use
Drugs that affect sinus node function or AV node conduction (e.g., digitalis, calcium channel blockers, beta blockers)	Potentiate bradycardia and risk of AV block	Avoid use

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Table 3: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Indinavir (See PRECAUTIONS, Table 9 for Recommended Alterations in Dose or Regimen)
Coadministered drug	Dose of Coadministered drug (mg)	Dose of CRIXIVAN (mg)	n	Ratio (with/without CRIXIVAN) of Coadministered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00
				C_max	AUC	C_min
All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
Clarithromycin	500 twice daily, 7 days	800 three times daily, 7 days	12	1.19 (1.02, 1.39)	1.47 (1.30, 1.65)	1.97 (1.58, 2.46) n=11
Efavirenz	200 once daily, 14 days	800 three times daily, 14 days	20	No significant change	No significant change	--
Ethinyl Estradiol (ORTHO-NOVUM 1/35)Registered trademark of Ortho Pharmaceutical Corporation.	35 mcg, 8 days	800 three times daily, 8 days	18	1.02 (0.96, 1.09)	1.22 (1.15, 1.30)	1.37 (1.24, 1.51)
Isoniazid	300 once daily in the morning, 8 days	800 three times daily, 8 days	11	1.34 (1.12, 1.60)	1.12 (1.03, 1.22)	1.00 (0.92, 1.08)
MethadoneStudy conducted in subjects on methadone maintenance.	20-60 once daily in the morning, 8 days	800 three times daily, 8 days	12	0.93 (0.84, 1.03)	0.96 (0.86, 1.06)	1.06 (0.94, 1.19)
Norethindrone (ORTHO-NOVUM 1/35)	1 mcg, 8 days	800 three times daily, 8 days	18	1.05 (0.95, 1.16)	1.26 (1.20, 1.31)	1.44 (1.32, 1.57)
Rifabutin 150 mg once daily in the morning, 11 days + indinavir compared to 300 mg once daily in the morning, 11 days alone	150 once daily in the morning, 10 days 300 once daily in the morning, 10 days	800 three times daily, 10 days 800 three times daily, 10 days	14 10	1.29 (1.05, 1.59) 2.34 (1.64, 3.35)	1.54 (1.33, 1.79) 2.73 (1.99, 3.77)	1.99 (1.71, 2.31) n=13 3.44 (2.65, 4.46) n=9
Ritonavir	100 twice daily, 14 days	800 twice daily, 14 days	10, 4Parallel group design; n for coadministered drug + indinavir, n for coadministered drug alone.	1.61 (1.13, 2.29)	1.72 (1.20, 2.48)	1.62 (0.93, 2.85)
	200 twice daily, 14 days	800 twice daily, 14 days	9, 5	1.19 (0.85, 1.66)	1.96 (1.39, 2.76)	4.71 (2.66, 8.33) n=9, 4
Saquinavir
Hard gel formulation	600 single dose	800 three times daily, 2 days	6	4.7 (2.7, 8.1)	6.0 (4.0, 9.1)	2.9 (1.7, 4.7)C_6hr
Soft gel formulation	800 single dose	800 three times daily, 2 days	6	6.5 (4.7, 9.1)	7.2 (4.3, 11.9)	5.5 (2.2, 14.1)
Soft gel formulation	1200 single dose	800 three times daily, 2 days	6	4.0 (2.7, 5.9)	4.6 (3.2, 6.7)	5.5 (3.7, 8.3)
Sildenafil	25 single dose	800 three times daily	6	See text below for discussion of interaction.
StavudineStudy conducted in HIV-positive subjects.	40 twice daily, 7 days	800 three times daily, 7 days	13	0.86 (0.73, 1.03)	1.21 (1.09, 1.33)	Not Done
Theophylline	250 single dose (on Days 1 and 7)	800 three times daily, 6 days (Days 2 to 7)	12, 4	0.88 (0.76, 1.03)	1.14 (1.04, 1.24)	1.13 (0.86, 1.49) n=7, 3
Trimethoprim/ Sulfamethoxazole
Trimethoprim	800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days	400 q6h, 7 days	12	1.18 (1.05, 1.32)	1.18 (1.05, 1.33)	1.18 (1.00, 1.39)
Trimethoprim/ Sulfamethoxazole
Sulfamethoxazole	800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days	400 q6h, 7 days	12	1.01 (0.95, 1.08)	1.05 (1.01, 1.09)	1.05 (0.97, 1.14)
Vardenafil	10 single dose	800 three times daily	18	See text below for discussion of interaction.
Zidovudine	200 three times daily, 7 days	1000 three times daily, 7 days	12	0.89 (0.73, 1.09)	1.17 (1.07, 1.29)	1.51 (0.71, 3.20) n=4
Zidovudine/ Lamivudine
Zidovudine	200/150 three times daily, 7 days	800 three times daily, 7 days	6, 7	1.23 (0.74, 2.03)	1.39 (1.02, 1.89)	1.08 (0.77, 1.50) n=5, 5
Zidovudine/ Lamivudine
Lamivudine	200/150 three times daily, 7 days	800 three times daily, 7 days	6, 7	0.73 (0.52, 1.02)	0.91 (0.66, 1.26)	0.88 (0.59, 1.33)

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^a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
^b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Bleeding times
Clinical Impact:	Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention:	This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact:	The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention:	Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact:	Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention:	This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
	? CBZ epoxide	May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Bleeding times
Clinical Impact:	Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention:	This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact:	The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention:	Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact:	Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention:	This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 Inhibitors, (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with ezetimibe and simvastatin tablets
Verapamil, diltiazem, dronedarone	Do not exceed ezetimibe and simvastatin tablets, 10 mg/10 mg daily
Amiodarone, amlodipine, ranolazine	Do not exceed ezetimibe and simvastatin tablets, 10 mg/20 mg daily
Lomitapide	For patients with HoFH, do not exceed 10 mg/20 mg ezetimibe and simvastatin tablets¹
Grapefruit juice	Avoid grapefruit juice

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Table 4: Drugs Having Clinically Important Interactions with Amphetamines
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact	Concomitant use of MAOIs and CNS stimulants can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure.
Intervention	Do not administer ADDERALL XR concomitantly or within 14 days after discontinuing MAOI [see CONTRAINDICATIONS (4) and WARNINGS AND PRECAUTIONS (5.6)].
Examples	selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
Serotonergic Drugs
Clinical Impact	The concomitant use of ADDERALL XR and serotonergic drugs increases the risk of serotonin syndrome.
Intervention	Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome, particularly during ADDERALL XR initiation or dosage increase. If serotonin syndrome occurs, discontinue ADDERALL XR and the concomitant serotonergic drug(s) [see WARNINGS AND PRECAUTIONS (5.6)].
Examples	selective serotonin reuptake inhibitors (SSRI), serotonin norepinephrine reuptake inhibitors (SNRI), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John's Wort
CYP2D6 Inhibitors
Clinical Impact	The concomitant use of ADDERALL XR and CYP2D6 inhibitors may increase the exposure of ADDERALL XR compared to the use of the drug alone and increase the risk of serotonin syndrome.
Intervention	Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome particularly during ADDERALL XR initiation and after a dosage increase. If serotonin syndrome occurs, discontinue ADDERALL XR and the CYP2D6 inhibitor [see WARNINGS AND PRECAUTIONS (5.6) and OVERDOSAGE (10)].
Examples	paroxetine and fluoxetine (also serotonergic drugs), quinidine, ritonavir
Alkalinizing Agents
Clinical Impact	Increase blood levels and potentiate the action of amphetamine.
Intervention	Co-administration of ADDERALL XR and gastrointestinal or urinary alkalinizing agents should be avoided.
Examples	Gastrointestinal alkalinizing agents (e.g., sodium bicarbonate). Urinary alkalinizing agents (e.g. acetazolamide, some thiazides).
Acidifying Agents
Clinical Impact	Lower blood levels and efficacy of amphetamines.
Intervention	Increase dose based on clinical response.
Examples	Gastrointestinal acidifying agents (e.g., guanethidine, reserpine, glutamic acid HCl, ascorbic acid). Urinary acidifying agents (e.g., ammonium chloride, sodium acid phosphate, methenamine salts).
Tricyclic Antidepressants
Clinical Impact	May enhance the activity of tricyclic or sympathomimetic agents causing striking and sustained increases in the concentration of d-amphetamine in the brain; cardiovascular effects can be potentiated.
Intervention	Monitor frequently and adjust or use alternative therapy based on clinical response.
Examples	desipramine, protriptyline
Proton Pump Inhibitors
Clinical Impact	Time to maximum concentration (Tmax) of amphetamine is decreased compared to when administered alone.
Intervention	Monitor patients for changes in clinical effect and adjust therapy based on clinical response.
Examples	omeprazole

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, gemfibrozil, cyclosporine,danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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Table 5: Effect of Other Drugs on VYVANSE
Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Acidifying and Alkalinizing Agents	Ascorbic acid and other agents that acidify urine increase urinary excretion and decrease the half-life of amphetamine. Sodium bicarbonate and other agents that alkalinize urine decrease urinary excretion and extend the half-life of amphetamine.	Adjust the dose accordingly [see Dosage and Administration (2.6)]

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Table 2: Clinically Relevant Interactions Affecting Drugs Co-Administered with Rabeprazole Sodium Delayed-Release Tablets
Antiretrovirals
Clinical Impact:	The effect of PPI on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and nelfinavir) when used concomitantly with rabeprazole may reduce antiviral effect and promote the development of drug resistance. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with rabeprazole may increase toxicity. There are other antiretroviral drugs which do not result in clinically relevant interactions with rabeprazole.
Intervention:	Rilpivirine-containing products: Concomitant use with rabeprazole sodium rabeprazole sodium delayed-release tablets is contraindicated [see Contraindications (4)]. See prescribing information. Atazanavir: See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with rabeprazole sodium delayed-release tablets. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir and monitor for potential saquinavir toxicities. Other antiretrovirals: See prescribing information.
Warfarin
Clinical Impact:	Increased INR and prothrombin time in patients receiving PPIs, including rabeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death [see Warnings and Precautions (5.2)].
Intervention:	Monitor INR and prothrombin time. Dose adjustment of warfarin may be needed to maintain target INR range. See prescribing information for warfarin.
Methotrexate
Clinical Impact:	Concomitant use of rabeprazole with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of methotrexate with PPIs have been conducted [see Warnings and Precautions (5.9)].
Intervention:	A temporary withdrawal of rabeprazole sodium delayed-release tablets may be considered in some patients receiving high dose methotrexate administration.
Digoxin
Clinical Impact:	Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention:	Monitor digoxin concentrations. Dose adjustment of digoxin may be needed to maintain therapeutic drug concentrations. See prescribing information for digoxin.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole, itraconazole)
Clinical Impact:	Rabeprazole can reduce the absorption of drugs due to its effect on reducing intragastric acidity.
Intervention:	Mycophenolate mofetil (MMF): Co-administration of PPIs in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving PPIs and MMF. Use rabeprazole sodium delayed-release tablets with caution in transplant patients receiving MMF. See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:	Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:	See Contraindications and Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.

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Table 5. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g.,Itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs that Interfere with Hemostasis
Clinical Impact:	Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of MOBIC with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions ( 5.11) ].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions ( 5.2) ].
Intervention:	Concomitant use of MOBIC and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions ( 5.11) ]. MOBIC is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, or Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of MOBIC and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of MOBIC and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions ( 5.6) ]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention:	During concomitant use of MOBIC with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see Warnings and Precautions ( 5.6) ].
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [ see Clinical Pharmacology ( 12.3) ].
Intervention:	During concomitant use of MOBIC and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of MOBIC and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of MOBIC and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention:	During concomitant use of MOBIC and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions ( 5.2) ].
Intervention:	The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of MOBIC and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of MOBIC and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.

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Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs that Interfere with Hemostasis
Clinical Impact:	Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention:	Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, or Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention:	During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology (12.3)].
Intervention:	During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention:	The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.

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Table II. Clinically significant drug interactions with theophylline^*.
Drug	Type of Interaction	Effect ^**
Adenosine	Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.
Alcohol	A single large dose of alcohol (3 ml/kg of whiskey) decreases theophylline clearance for up to 24 hours.	30% increase
Allopurinol	Decreases theophylline clearance at allopurinol doses ≥600 mg/day.	25% increase
Aminoglutethimide	Increases theophylline clearance by induction of microsomal enzyme activity.	25% decrease
Carbamazepine	Similar to aminoglutethimide.	30% decrease
Cimetidine	Decreases theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase
Ciprofloxacin	Similar to cimetidine.	40% increase
Clarithromycin	Similar to erythromycin.	25% increase
Diazepam	Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.	Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram	Decreases theophylline clearance by inhibiting hydroxylation and demethylation.	50% increase
Enoxacin	Similar to cimetidine.	300% increase
Ephedrine	Synergistic CNS effects.	Increased frequency of nausea, nervousness, and insomnia.
Erythromycin	Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen	Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.	30% increase
Flurazepam	Similar to diazepam.	Similar to diazepam.
Fluvoxamine	Similar to cimetidine.	Similar to cimetidine.
Halothane	Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.	Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A	Decreases theophylline clearance.	100% increase
Isoproterenol (IV)	Increases theophylline clearance.	20% decrease
Ketamine	Pharmacologic	May lower theophylline seizure threshold.
Lithium	Theophylline increases renal lithium clearance.	Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam	Similar to diazepam.	Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.	20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine	Similar to disulfiram.	80% increase
Midazolam	Similar to diazepam.	Similar to diazepam.
Moricizine	Increases theophylline clearance.	25% decrease
Pancuronium	Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.	Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline	Decreases theophylline clearance.	30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.	25% decrease after two weeks of concurrent PB.
Phenytoin	Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.	Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone	Decreases theophylline clearance and pharmacologic interaction.	40% increase. Beta-₂ blocking effect may decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and pharmacologic interaction.	100% increase. Beta-₂ blocking effect may decrease efficacy of theophylline.
Rifampin	Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.	20 to 40% decrease
Sulfinpyrazone	Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.	20% decrease
Tacrine	Similar to cimetidine, also increases renal clearance of theophylline.	90% increase
Thiabendazole	Decreases theophylline clearance.	190% increase
Ticlopidine	Decreases theophylline clearance.	60% increase
Troleandomycin	Similar to erythromycin.	33 to 100% increase depending on troleandomycin dose.
Verapamil	Similar to disulfiram.	20% increase
Refer to PRECAUTIONS, Drug Interactions for further information regarding table. ^* Average effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.

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^*For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily*
Grapefruit juice	Avoid grapefruit juice

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Figure 2: Effect of venlafaxine on the pharmacokinetics interacting drugs and their active metabolites.

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Summary of AED interactions with topiramate ( 7.1).
AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase ^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide ^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400mg/day	13% decrease

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Table 5. Drugs That May Decrease Conversion of T4 to T3
Potential impact: Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased.
Drug or Drug Class	Effect
Beta-adrenergic antagonists (e.g., Propranolol > 160 mg/day)	In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change, TSH levels remain normal, and patients are clinically euthyroid. Actions of particular beta-adrenergic antagonists may be impaired when a hypothyroid patient is converted to the euthyroid state.
Glucocorticoids (e.g., Dexamethasone > 4 mg/day)	Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (See above).
Other drugs: Amiodarone	Amiodarone inhibits peripheral conversion of levothyroxine (T4) to triiodothyronine (T3) and may cause isolated biochemical changes (increase in serum free-T4, and decreased or normal free-T3) in clinically euthyroid patients.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. ₄ ₃
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT , is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. ₄ ₄ ₄ ₄ ₃ ₄ ₄ ₄
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. ₄
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T to T , leading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T and T levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). ₄ ₃ ₃ ₄ ₃ ₄ ₃ ₄ ₃ ₄
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of I, I, and Tc. ¹²³ ¹³¹ ^99m
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 2 Effects of Paroxetine on Other Drugs
Concomitant Drug Name	Effect of Paroxetine on Other Drugs	Clinical Recommendations
Thioridazine	Increased plasma concentrations of thioridazine Potential QTc prolongation	Concomitant use of thioridazine and BRISDELLE is contraindicated.
Pimozide	Increased plasma concentrations of pimozide. Potential QTc prolongation	Concomitant use of pimozide and BRISDELLE is contraindicated.
Tamoxifen	Reduced plasma concentrations of active tamoxifen metabolite	Consider avoiding concomitant use of tamoxifen and BRISDELLE.
Tricyclic Antidepressant (TCA) (e.g., Desipramine)	Increased plasma concentrations and elimination half-life	Plasma TCA concentrations may need to be monitored and the dose of TCA may need to be reduced if a TCA is co-administered with BRISDELLE. Monitor tolerability.
Risperidone	Increased plasma concentrations of risperidone	A lower dosage of risperidone may be necessary (see the Full Prescribing Information for risperidone). Monitor tolerability.
Atomoxetine	Increased exposure of atomoxetine	A lower dosage of atomoxetine may be necessary (see Full Prescribing Information for atomoxetine). Monitor tolerability.
Drugs Highly Bound to Plasma Protein (e.g., Warfarin)	Increased free plasma concentrations	The dosage of warfarin may need to be reduced. Monitor tolerability and the International Normalized Ratio.
Digoxin	Decreased plasma concentrations of digoxin	Dosage of digoxin may need to be increased. Monitor digoxin concentrations and clinical effect.
Theophylline	Increased plasma concentrations of theophylline	Dosage of theophylline may need to be decreased. Monitor theophylline concentrations and tolerability.

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Drug	Description of Interaction
Tolbutamide; Sulfonylureas	Hypoglycemia potentiated
Methotrexate	Decrease tubular reabsorption; clinical toxicity from methotrexate can result
Oral Anticoagulants	Increased bleeding

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AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide Is not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin	Monitor phenytoin level (7)
Methotrexate	Monitor for methotrexate toxicity (7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Antibiotics	Anticonvulsants	Other Drugs/DietarySupplements
nafcillin	carbamazepine	bosentan	St. John’s Wort
rifampin	oxcarbazepine	octreotide
	phenobarbital	orlistat
	phenytoin	sulfinpyrazone
		terbinafine
		ticlopidine

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine,danazol	Do not exceed 10 mg simvastatindaily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem	Do not exceed 40 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs that Interfere with Hemostasis
Clinical Impact :	Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention :	Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see WARNINGS AND PRECAUTIONS ( 5 . 11 )].
Aspirin
Clinical Impact :	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see WARNINGS AND PRECAUTIONS ( 5 . 2 )].
Intervention :	Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see WARNINGS AND PRECAUTIONS ( 5 . 11 )]. Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors , Angiotensin Receptor Blockers , or Beta - Blockers
Clinical Impact :	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention :	During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see WARNINGS AND PRECAUTIONS ( 5 . 6 )]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact :	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention :	During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see WARNINGS AND PRECAUTIONS ( 5 . 6 )].
Lithium
Clinical Impact :	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [ see CLINICAL PHARMACOLOGY ( 12 . 3 )].
Intervention :	During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact :	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention :	During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact :	Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention :	During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact :	Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see WARNINGS AND PRECAUTIONS ( 5 . 2 )].
Intervention :	The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact :	Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention :	During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.

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Table 8: Clinically Significant Drug Interactions with LANTUS
Drugs That May Increase the Risk of Hypoglycemia
Drugs:	Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics.
Intervention:	Dose reductions and increased frequency of glucose monitoring may be required when LANTUS is co-administered with these drugs.
Drugs That May Decrease the Blood Glucose Lowering Effect of LANTUS
Drugs:	Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones
Intervention:	Dose increases and increased frequency of glucose monitoring may be required when LANTUS is co-administered with these drugs.
Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of LANTUS
Drugs:	Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.
Intervention:	Dose adjustment and increased frequency of glucose monitoring may be required when LANTUS is co-administered with these drugs.
Drugs That May Blunt Signs and Symptoms of Hypoglycemia
Drugs:	beta-blockers, clonidine, guanethidine, and reserpine
Intervention:	Increased frequency of glucose monitoring may be required when LANTUS is co-administered with these drugs.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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AED Co - administered	AED Concentration	Topiramate Concentration
Phenytoin	NCor25%increase ^a	48%decrease
Carbamazepine(CBZ)	NC	40%decrease
CBZepoxide ^b	NC	NE
Valproic acid	11%decrease	14%decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NCatTPM dosesupto400 mg/day	13%decrease

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Table 6 Clinically Important Drug Interactions
Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Tricyclic antidepressants	Increase blood pressure and may counteract clonidine’s hypotensive effects	Monitor blood pressure and adjust as needed
Antihypertensive drugs	Potentiate clonidine’s hypotensive effects	Monitor blood pressure and adjust as needed
CNS depressants	Potentiate sedating effects	Avoid use
Drugs that affect sinus node function or AV node conduction (e.g., digitalis, calcium channel blockers, beta blockers)	Potentiate bradycardia and risk of AV block	Avoid use

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Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name:

Table 5. Sevelamer Drug Interactions
Oral drugs for which sevelamer did not alter the pharmacokinetics when administered concomitantly
Digoxin Enalapril Iron Metoprolol Warfarin
Oral drugs that have demonstrated interaction with sevelamer and are to be dosed separately from sevelamer carbonate
Ciprofloxacin Mycophenolate mofetil	Dosing Recommendations Take at least 2 hours before or 6 hours after sevelamer Take at least 2 hours before sevelamer

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Table 6: Summary of drug-drug interactions of BANZEL with other antiepileptic drugs
AED Co-administered	Influence of Rufinamide on AED concentration ^a)	Influence of AED on Rufinamide concentration
Carbamazepine	Decrease by 7 to 13%^b)	Decrease by 19 to 26% Dependent on dose of carbamazepine
Lamotrigine	Decrease by 7 to 13%^b)	No Effect
Phenobarbital	Increase by 8 to 13%^b)	Decrease by 25 to 46%^c) _’ ^d) Independent of dose or concentration of phenobarbital
Phenytoin	Increase by 7 to 21%^b)	Decrease by 25 to 46%^c) _’ ^d) Independent of dose or concentration of phenytoin
Topiramate	No Effect	No Effect
Valproate	No Effect	Increase by <16 to 70%^c) Dependent on concentration of valproate
Primidone	Not Investigated	Decrease by 25 to 46%^c) _’ ^d) Independent of dose or concentration of primidone
Benzodiazepines ^e)	Not Investigated	No Effect
a) Predictions are based on BANZEL concentrations at the maximum recommended dose of BANZEL. b) Maximum changes predicted to be in pediatric patients and in adult patients who achieve significantly higher levels of BANZEL, as the effect of rufinamide on these AEDs is concentration-dependent. c) Larger effects in pediatric patients at high doses/concentrations of AEDs. d) Phenobarbital, primidone and phenytoin were treated as a single covariate (phenobarbital-type inducers) to examine the effect of these agents on BANZEL clearance. e) All compounds of the benzodiazepine class were pooled to examine for ‘class effect’ on BANZEL clearance.

Table name:

Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin	Monitor phenytoin level (7)
Methotrexate	Monitor for methotrexate toxicity (7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)

Table name:

Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name:

Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol,	famotidine	nizatidine
systemic and inhaled	felodipine	norfloxacin
amoxicillin	finasteride	ofloxacin
ampicillin,	hydrocortisone	omeprazole
with or without	isoflurane	prednisone, prednisolone
sulbactam	isoniazid	ranitidine
atenolol	isradipine	rifabutin
azithromycin	influenza vaccine	roxithromycin
caffeine,	ketoconazole	sorbitol
dietary ingestion	lomefloxacin	(purgative doses do not
cefaclor	mebendazole	inhibit theophylline
co-trimoxazole	medroxyprogesterone	absorption)
(trimethoprim and	methylprednisolone	sucralfate
sulfamethoxazole)	metronidazole	terbutaline, systemic
diltiazem	metoprolol	terfenadine
dirithromycin	nadolol	tetracycline
enflurane	nifedipine	tocainide

Table name: Drugs That Interfere with HemostasisClinical Impact:• Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.Intervention:Monitor patients with concomitant use of VOLTAREN^® GEL with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].AspirinClinical Impact:Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].Intervention:Concomitant use of VOLTAREN^® GEL and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. VOLTAREN^® GEL is not a substitute for low dose aspirin for cardiovascular protection.ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-BlockersClinical Impact:• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.Intervention:• During concomitant use of VOLTAREN^® GEL and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of VOLTAREN^® GEL and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.DiureticsClinical Impact:Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.Intervention:During concomitant use of VOLTAREN^® GEL with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].DigoxinClinical Impact:The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.Intervention:During concomitant use of VOLTAREN^® GEL and digoxin, monitor serum digoxin levels.LithiumClinical Impact:NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.During concomitant use of VOLTAREN^® GEL and lithium, monitor patients for signs of lithium toxicity.MethotrexateClinical Impact:Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).Intervention:During concomitant use of VOLTAREN^® GEL and methotrexate, monitor patients for methotrexate toxicity.CyclosporineClinical Impact:Concomitant use of VOLTAREN^® GEL and cyclosporine may increase cyclosporine's nephrotoxicity.Intervention:During concomitant use of VOLTAREN^® GEL and cyclosporine, monitor patients for signs of worsening renal function.NSAIDs and SalicylatesClinical Impact:Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].Intervention:The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.PemetrexedClinical Impact:Concomitant use of VOLTAREN^® GEL and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).Intervention:During concomitant use of VOLTAREN^® GEL and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and Gl toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.






























Intervention:

Table name:

Digoxin concentrations increased greater than 50%
	Digoxin Serum Concentration Increase	Digoxin AUC Increase	Recommendations
Quinidine	NA	54-83%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
Ritonavir	NA	86%
Digoxin concentrations increased less than 50%
Amiodarone	17%	40%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15 to 30% or by modifying the dosing frequency and continue monitoring.
Propafenone	28%	29%
Quinine	NA	34-38%
Spironolactone	NA	44%
Verapamil	NA	24%

Table name:

Antiretrovirals
Clinical Impact:	The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3)]. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)]. There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
Intervention:	Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications (4)]. Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:	Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention:	Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact:	Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].
Intervention:	A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact:	Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)]. There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention:	Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6)].
Citalopram
Clinical Impact:	Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention:	Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:	Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].
Intervention:	Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:	Potential for increased exposure of phenytoin.
Intervention:	Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:	Increased exposure of diazepam [see Clinical Pharmacology (12.3)].
Intervention:	Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:	Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention:	Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:	Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:	Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)]. See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:	Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated.
	Amoxicillin also has drug interactions.
Intervention:	See Contraindications, Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact:	Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention:	Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:	Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10), Clinical Pharmacology (12.2)].
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:	Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact:	There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:	An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:	There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:	Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of this product. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

Table name:

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

Table name:

Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)	VIAGRA 50 mg (95% CI)
Supine	9.08 (5.48, 12.68)
Standing	11.62 (7.34, 15.90)

Table name:

Table 2: Clinically Significant Drug Interactions with Mefenamic Acid Drugs That Interfere with Hemostasis
Drugs That Interfere with Hemostasis
Clinical Impact:	• Mefenamic acid and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of mefenamic acid and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of mefenamic acid with anticoagulants (e.g.,warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS ; Hematologic Toxicity ).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation ).
Intervention:	Concomitant use of mefenamic acid and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS ; Hematologic Toxicity ). Mefenamic acid is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	• During concomitant use of mefenamic acid and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of mefenamic acid and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS ; Renal Toxicity and Hyperkalemia ). • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention	During concomitant use of mefenamic acid with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS ; Renal Toxicity and Hyperkalemia ).
Digoxin
Clinical Impact:	The concomitant use of mefenamic acid with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of mefenamic acid and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of mefenamic acid and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of mefenamic acid and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of mefenamic acid and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of mefenamic acid and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of mefenamic acid with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS ; Gastrointestinal Bleeding, Ulceration and Perforation ).
Intervention:	The concomitant use of mefenamic acid with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of mfenamic acid and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of mefenamic acid and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacid
Clinical Impact:	In a single dose study (n= 6), ingestion of an antacid containing 1.7-gram of magnesium hydroxide with 500-mg of mefenamic acid increased the Cmax and AUC of mefenamic acid by 125% and 36%, respectively.
Intervention:	Concomitant use of mefenamic acid and antacids is not generally recommended because of possible increased adverse events.

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Factors	Dosage Adjustments for Aripirazole Tablets
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors	Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double usual dose over 1 to 2 weeks

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Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy-Risperidone (RatioChange relative to reference)		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	C_max
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Reevaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Reevaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg 4 times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed

Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio Change relative to reference)		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	Cmax	Risperidone Dose Recommendation
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Table 4: Clinically Relevant Interactions Affecting Omeprazole When Co-Administered with Other Drugs
CYP2C19 or CYP3A4 Inducers
Clinical Impact:	Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology ( 12.3)].
Intervention:	St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions ( 5.9)]. Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:	Increased exposure of omeprazole [see Clinical Pharmacology ( 12.3)].
Intervention:	Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole.

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Table 4. Sevelamer Drug Interactions
Oral drugs for which sevelamer did not alter the pharmacokinetics when administered concomitantly
Digoxin Enalapril Iron Metoprolol Warfarin
Oral drugs that have demonstrated interaction with sevelamer and are to be dosed separately from Renagel
	Dosing Recommendations
Ciprofloxacin	Take at least 2 hours before or 6 hours after sevelamer
Mycophenolate mofetil	Take at least 2 hours before sevelamer

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine (CBZ) and CBZ epoxide	? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2 fold.
Valproate	? valproate	Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 7 Summary of AED Interactions with Oxcarbazepine
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400 to 2000	900	nc¹	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100 to 150	600 to 1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250 to 500	600 to 1800 >1200 to 2400	nc^1,2 up to 40% increase³ [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400 to 2800	600 to 1800	nc¹	18% decrease [CI: 13% decrease, 40% decrease]

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Inhibitors of CYP3A4
Clinical Impact:	The concomitant use of fentanyl transdermal system and CYP3A4 inhibitors can increase the plasma concentration of fentanyl, resulting in increased or prolonged opioid effects particularly when an inhibitor is added after a stable dose of fentanyl transdermal system is achieved [see Warnings and Precautions (5.5)]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl transdermal system plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to fentanyl.
Intervention:	If concomitant use is necessary, consider dosage reduction of fentanyl transdermal system until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the fentanyl transdermal system dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir), grape fruit juice
CYP3A4 Inducers
Clinical Impact:	The concomitant use of fentanyl transdermal system and CYP3A4 inducers can decrease the plasma concentration of fentanyl [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to fentanyl [see Warnings and Precautions (5.5)]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention:	If concomitant use is necessary, consider increasing the fentanyl transdermal system dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider fentanyl transdermal system dosage reduction and monitor for signs of respiratory depression.
Examples:	Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.7)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions 5.10].
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue fentanyl transdermal system if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.10)] or opioid toxicity (e.g., respiratory depression, coma).
Intervention:	The use of fentanyl transdermal system is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of fentanyl transdermal system and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Fentanyl transdermal system may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of fentanyl transdermal system and/or the muscle relaxant as necessary.

Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl transdermal system is used concomitantly with anticholinergic drugs.

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Table 12: Effect of Voriconazole on Pharmacokinetics of Other Drugs
Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C_max and AUC_τ)	Recommendations for Drug Dosage Adjustment/Comments
SirolimusResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
EfavirenzResults based on in vivo clinical study following repeat oral dosing with 400 mg Q12h for 1 day, then 200 mg Q12h for at least 2 days voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	When voriconazole is coadministered with efavirenz, voriconazole maintenance dose should be increased to 400 mg Q12h and efavirenz should be decreased to 300 mg Q24h (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION-Dosage Adjustment)
High-dose Ritonavir (400 mg Q12h)(CYP3A4 Inhibition)	No Significant Effect of Voriconazole on Ritonavir C_max or AUC_τ	Contraindicated because of significant reduction of voriconazole C_max and AUC_τ
Low-dose Ritonavir (100mg Q12h)	Slight Decrease in Ritonavir C_max and AUC_τ	Coadministration of voriconazole and low-dose ritonavir (100 mg Q12h) should be avoided (due to the reduction in voriconazole C_max and AUC_τ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated
Cyclosporine (CYP3A4 Inhibition)	AUC_τ Significantly Increased; No Significant Effect on C_max	When initiating therapy with VFEND in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
MethadoneResults based on in vivo clinical study following repeat oral dosing with 400 mg Q12h for 1 day, then 200 mg Q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30–100 mg QD) (CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary (see CLINICAL PHARMACOLOGY - Drug Interactions).
Tacrolimus (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)	Increased	Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects on Indinavir Exposure In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	No dosage adjustment for indinavir when coadministered with VFEND Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.

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Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of aripiprazole with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)] .	With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)] .
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)] .	With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)] .
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.7)] .
Benzodiazepines(e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.7)] .	Monitor sedation and blood pressure. Adjust dose accordingly.

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol,	famotidine	nizatidine
systemic and inhaled	felodipine	norfloxacin
amoxicillin	finasteride	ofloxacin
ampicillin,	hydrocortisone	omeprazole
with or without	isoflurane	prednisone, prednisolone
sulbactam	isoniazid	ranitidine
atenolol	isradipine	rifabutin
azithromycin	influenza vaccine	roxithromycin
caffeine,	ketoconazole	sorbitol
dietary ingestion	lomefloxacin	(purgative doses do not
cefaclor	mebendazole	inhibit theophylline
co-trimoxazole	medroxyprogesterone	absorption)
(trimethoprim and	methylprednisolone	sucralfate
sulfamethoxazole)	metronidazole	terbutaline, systemic
diltiazem	metoprolol	terfenadine
dirithromycin	nadolol	tetracycline
enflurane	nifedipine	tocainide

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Calcium Channel Blockers	Antifungals	Antibiotics	Glucocorticoids	Other Drugs
diltiazem	fluconazole	azithromycin	methylprednisolone	Allopurinol
nicardipine	itraconazole	clarithromycin		Amiodarone
verapamil	ketoconazole	erythromycin		Bromocriptine
	voriconazole	quinupristin/ dalfopristin		colchicine
				danazol
				imatinib
				metoclopramide
				nefazodone
				oral contraceptives

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Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of aripiprazole with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.7)].
Benzodiazepines(e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.7)].	Monitor sedation and blood pressure. Adjust dose accordingly.

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Summary of AED interactions with topiramate ( 7.1).
AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase ^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide ^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400mg/day	13% decrease

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Table 5. Established and Other Potentially Significant Drug Interactions
↓= Decreased (induces lamotrigine glucuronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓levonorgestrel	Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and Carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. ( 2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose ( 5.12, 7.3)

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Table 2 Effects of Paroxetine on Other Drugs
Concomitant Drug Name	Effect of Paroxetine on Other Drugs	Clinical Recommendations
Thioridazine	Increased plasma concentrations of thioridazine Potential QTc prolongation	Concomitant use of thioridazine and BRISDELLE is contraindicated.
Pimozide	Increased plasma concentrations of pimozide. Potential QTc prolongation	Concomitant use of pimozide and BRISDELLE is contraindicated.
Tamoxifen	Reduced plasma concentrations of active tamoxifen metabolite	Consider avoiding concomitant use of tamoxifen and BRISDELLE.
Tricyclic Antidepressant (TCA) (e.g., Desipramine)	Increased plasma concentrations and elimination half-life	Plasma TCA concentrations may need to be monitored and the dose of TCA may need to be reduced if a TCA is co-administered with BRISDELLE. Monitor tolerability.
Risperidone	Increased plasma concentrations of risperidone	A lower dosage of risperidone may be necessary (see the Full Prescribing Information for risperidone). Monitor tolerability.
Atomoxetine	Increased exposure of atomoxetine	A lower dosage of atomoxetine may be necessary (see Full Prescribing Information for atomoxetine). Monitor tolerability.
Drugs Highly Bound to Plasma Protein (e.g., Warfarin)	Increased free plasma concentrations	The dosage of warfarin may need to be reduced. Monitor tolerability and the International Normalized Ratio.
Digoxin	Decreased plasma concentrations of digoxin	Dosage of digoxin may need to be increased. Monitor digoxin concentrations and clinical effect.
Theophylline	Increased plasma concentrations of theophylline	Dosage of theophylline may need to be decreased. Monitor theophylline concentrations and tolerability.

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Bleeding times
Clinical Impact:	Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention:	This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact:	The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention:	Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact:	Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention:	This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.

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Table 7 Summary of AED Interactions with Oxcarbazepine
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400-2000	900	nc nc denotes a mean change of less than 10%	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100-150	600-1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250-500	600-1800 >1200-2400	nc Pediatrics up to 40% increase [CI: 12% increase, Mean increase in adults at high oxcarbazepine doses 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400-2800	600-1800	nc	18% decrease [CI: 13% decrease, 40% decrease]

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Amiodarone, verapamil, diltiazem	Do not exceed 10 mg simvastatin daily
Amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, Posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine,danazol	Contraindicated with simvastatin
Verapamil, diltiazem	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
* For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily*
Grapefruit juice	Avoid grapefruit juice

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Table II. Clinically significant drug interactions with theophylline.Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
Drug	Type of Interaction	EffectAverage effect on steady-state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine	Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.
Alcohol	A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours.	30% increase
Allopurinol	Decreases theophylline clearance at allopurinol doses ≥600 mg/day.	25% increase
Aminoglutethimide	Increases theophylline clearance by induction of microsomal enzyme activity.	25% decrease
Carbamazepine	Similar to aminoglutethimide.	30% decrease
Cimetidine	Decreases theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase
Ciprofloxacin	Similar to cimetidine.	40% increase
Clarithromycin	Similar to erythromycin.	25% increase
Diazepam	Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.	Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram	Decreases theophylline clearance by inhibiting hydroxylation and demethylation.	50% increase
Enoxacin	Similar to cimetidine.	300% increase
Ephedrine	Synergistic CNS effects	Increased frequency of nausea, nervousness, and insomnia.
Erythromycin	Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen	Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.	30% increase
Flurazepam	Similar to diazepam.	Similar to diazepam.
Fluvoxamine	Similar to cimetidine.	Similar to cimetidine.
Halothane	Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.	Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A	Decreases theophylline clearance.	100% increase
Isoproterenol (IV)	Increase theophylline clearance.	20% increase
Ketamine	Pharmacologic	May lower theophylline seizure threshold.
Lithium	Theophylline increases renal lithium clearance.	Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam	Similar to diazepam.	Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.	20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine	Similar to disulfiram.	80% increase
Midazolam	Similar to diazepam.	Similar to diazepam.
Moricizine	Increases theophylline clearance.	25% decrease
Pancuronium	Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.	Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline	Decreases theophylline clearance.	30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.	25% decrease after two weeks of concurrent PB.
Phenytoin	Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.	Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone	Decreases theophylline clearance and pharmacologic interaction.	40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and pharmacologic interaction.	100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin	Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.	20 to 40% decrease
Sulfinpyrazone	Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.	20% increase
Tacrine	Similar to cimetidine, also increases renal clearance of theophylline.	90% increase
Thiabendazole	Decreases theophylline clearance.	190% increase
Ticlopidine	Decreases theophylline clearance.	60% increase
Troleandomycin	Similar to erythromycin.	33 to 100% increase depending on troleandomycin dose.
Verapamil	Similar to disulfiram.	20% increase

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Figure 2: Effect of venlafaxine on the pharmacokinetics interacting drugs and their active metabolites.

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Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
*Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	Cmax
Enzyme (CYP2D6) inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not Needed

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T ₄ and T ₃levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT ₄ . Continued administration results in a decrease in serum T ₄ and normal FT ₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T ₄ and T ₃ to TBG and transthyretin. An initial increase in serum FT ₄ is followed by return of FT ₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T ₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T ₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T ₄ to T ₃, leading to decreased T ₃ levels. However, serum T ₄levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T ₃ and T ₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T ₃concentrations by 30% with minimal change in serum T ₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T ₃ and T ₄levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³ I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
*Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	C_m _a _x
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing.
	20 mg/day	4 mg/day	1.6	-	Do not exceed 8 mg/day
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers)
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Table 13. Established and Other Potentially Significant Drug Interactions
↓= Decreased (induces lamotrigine glucuronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
?= Conflicting data.
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Effects on Steady-State Fexofenadine Pharmacokinetics After 7 Days of Co-Administration with Fexofenadine Hydrochloride 120 mg Every 12 Hours (two times the recommended twice daily dose) in Healthy Volunteers (n=24)
Concomitant Drug	C_{max SS} (Peak plasma concentration)	AUC_SS(0–12h) (Extent of systemic exposure)
Erythromycin (500 mg every 8 hrs)	+82%	+109%
Ketoconazole (400 mg once daily)	+135%	+164%

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Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Table 1 Oral drugs that can be administered concomitantly with Velphoro
Calcitriol Ciprofloxacin Digoxin Enalapril Furosemide HMG-CoA reductase inhibitors Hydrochlorothiazide Losartan Metoprolol Nifedipine Omeprazole Quinidine Warfarin
Oral drugs that are to be separated from Velphoro and meals
	Dosing Recommendations
Doxycycline	Take at least 1 hour before Velphoro.
Oral drugs that should not be prescribed with Velphoro
Levothyroxine

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Interacting DrugInteracting Drug	InteractionInteraction
Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products ( 2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents	Carefully monitor blood glucose ( 5.12, 7.3)

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Drugs that Affect Renal Function	A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics	Dofetilide	Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
	Sotalol	Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
	Dronedarone	Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog	Teriparatide	Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement	Thyroid	Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics	Epinephrine Norepinephrine Dopamine	Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents	Succinylcholine	May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements	Calcium	If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers		Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.

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Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Interacting DrugInteracting Drug	InteractionInteraction
Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products.
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents	Carefully monitor blood glucose ( 5.11, 7.3)

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Table 1: Clinically Significant Drug Interactions with Morphine Sulfate Injection
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Morphine Sulfate Injection if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.7)].
Intervention:	Do not use Morphine Sulfate Injection in patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of other opioids (such as oxycodone, hydrocodone, oxymorphone, hydrocodone, or buprenorphine) to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of Morphine Sulfate Injection and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine.

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Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Inhibitors of CYP2D6
Clinical Impact:	The concomitant use of tramadol hydrochloride and acetaminophen and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride and acetaminophen is achieved. Since M1 is a more potent µ-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease and the M1 plasma concentration will increase which could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, and may cause potentially fatal respiratory depression [see Clinical Pharmacology ( 12.3)] .
Intervention:	If concomitant use of a CYP2D6 inhibitor is necessary, follow patients closely for adverse reactions including opioid withdrawal, seizures and serotonin syndrome. If a CYP2D6 inhibitor is discontinued, consider lowering tramadol hydrochloride and acetaminophen dosage until stable drug effects are achieved. Follow patients closely for adverse events including respiratory depression and sedation.
Examples	Quinidine, fluoxetine, paroxetine and bupropion
Inhibitors of CYP3A4
Clinical Impact:	The concomitant use of tramadol hydrochloride and acetaminophen and CYP3A4 inhibitors can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1. Follow patients closely for increased risk of serious adverse events including seizures and serotonin syndrome, and adverse reactions related to opioid toxicity including potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride and acetaminophen is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease [see Clinical Pharmacology ( 12.3)] , resulting in decreased opioid efficacy and possibly signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol.
Intervention:	If concomitant use is necessary, consider dosage reduction of tramadol hydrochloride and acetaminophen until stable drug effects are achieved. Follow patients closely for seizures and serotonin syndrome, and signs of respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the tramadol hydrochloride and acetaminophen dosage until stable drug effects are achieved and follow patients for signs and symptoms of opioid withdrawal.
Examples	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact:	The concomitant use of tramadol hydrochloride and acetaminophen and CYP3A4 inducers can decrease the plasma concentration of tramadol [see Clinical Pharmacology ( 12.3)] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase [see Clinical Pharmacology ( 12.3)] , which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression, seizures and serotonin syndrome.
Intervention:	If concomitant use is necessary, consider increasing the tramadol hydrochloride and acetaminophen dosage until stable drug effects are achieved. Follow patients for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider tramadol hydrochloride and acetaminophen dosage reduction and monitor for seizures and serotonin syndrome, and signs of sedation and respiratory depression. Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of tramadol hydrochloride and acetaminophen and carbamazepine is not recommended.
Examples:	Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions ( 5.6)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue tramadol hydrochloride and acetaminophen if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions ( 5.7)] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions ( 5.2)] .
Intervention:	Do not use tramadol hydrochloride and acetaminophen in patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of tramadol hydrochloride and acetaminophen and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Tramadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of tramadol hydrochloride and acetaminophen and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when tramadol hydrochloride and acetaminophen is used concomitantly with anticholinergic drugs.
Digoxin
Clinical Impact:	Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity.
Intervention:	Follow patients for signs of digoxin toxicity and adjust dosage of digoxin as needed.
Warfarin
Clinical Impact:	Post-marketing surveillance of tramadol has revealed rare reports of alteration of warfarin effect, including elevation of prothrombin times.
Intervention:	Monitor the prothrombin time of patients on warfarin for signs of an interaction and adjust the dosage of warfarin as needed.

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Table 4. The Effect of CRESEMBA on the Pharmacokinetics of Other Drugs
^a400 mg of lopinavir in combination with 100 mg of ritonavir.
	Recommendation	Comments
Lopinavir/ritonavir^a	Use with Caution	Concomitant administration of lopinavir/ritonavir and CRESEMBA resulted in decreased exposure of lopinavir and ritonavir that could possibly result in loss of antiviral efficacy [see Clinical Pharmacology (12.3)].
Atorvastatin	Use with Caution	Caution should be used when atorvastatin is used with CRESEMBA due to a potential increase in atorvastatin exposure. Monitor patients for adverse reactions that are typical of atorvastatin.
Cyclosporine	Use with Caution	Concomitant administration of CRESEMBA and cyclosporine results in increase in cyclosporine exposure. Monitor drug concentrations of cyclosporine and adjust dose as needed [see Clinical Pharmacology (12.3)].
Sirolimus	Use with Caution	Concomitant administration of CRESEMBA and sirolimus results in increase in sirolimus exposure. Monitor drug concentrations of sirolimus and adjust dose as needed [see Clinical Pharmacology (12.3)].
Tacrolimus	Use with Caution	Concomitant administration of CRESEMBA and tacrolimus results in increase in tacrolimus exposure. Monitor drug concentrations of tacrolimus and adjust dose as needed [see Clinical Pharmacology (12.3)].
Midazolam	Use with Caution	Concomitant administration of CRESEMBA and midazolam results in increase in midazolam exposure. Consider dose reduction of midazolam when isavuconazole is coadministered [see Clinical Pharmacology (12.3)].
Bupropion	Use with Caution	Concomitant administration of CRESEMBA and bupropion results in decrease in bupropion exposure. Dose increase of bupropion may be necessary when coadministered with CRESEMBA, but should not exceed the maximum recommended dose [see Clinical Pharmacology (12.3)].
Mycophenolate Mofetil	Use with Caution	Concomitant administration of CRESEMBA and MMF results in increase in MMF exposure. Patients receiving CRESEMBA concurrently with MMF should be monitored for MPA-related toxicities [see Clinical Pharmacology (12.3)].
Digoxin	Use with Caution	Concomitant administration of CRESEMBA and digoxin results in increase in digoxin exposure. Serum digoxin concentrations should be monitored and used for titration when dosed concurrently with CRESEMBA [see Clinical Pharmacology (12.3)].

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Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs that Interfere with Hemostasis
Clinical Impact:	Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of MOBIC with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention:	Concomitant use of MOBIC and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. MOBIC is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, or Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of MOBIC and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of MOBIC and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention:	During concomitant use of MOBIC with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology (12.3)].
Intervention:	During concomitant use of MOBIC and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of MOBIC and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of MOBIC and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention:	During concomitant use of MOBIC and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention:	The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of MOBIC and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of MOBIC and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir )	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin	Monitor phenytoin level (7)
Methotrexate	Monitor for methotrexate toxicity (7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)

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Table 5. Clinically-Significant Drug Interactions with Sertraline Hydrochloride
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	The concomitant use of SSRIs including sertraline hydrochloride and MAOIs increases the risk of serotonin syndrome.
Intervention:	Sertraline hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [See Dosage and Administration (2.5), Contraindications (4), Warnings and Precautions (5.2)].
Examples:	selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
Pimozide
Clinical Impact:	Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QT prolongation and ventricular arrhythmias.
Intervention:	Concomitant use of pimozide and sertraline hydrochloride is contraindicated [See Contraindications (4)].
Other Serotonergic Drugs
Clinical Impact:	The concomitant use of serotonergic drugs with sertraline hydrochloride increases the risk of serotonin syndrome.
Intervention:	Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of sertraline hydrochloride and/or concomitant serotonergic drugs [See Warnings and Precautions (5.2)].
Examples:	other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort
Drugs that Interfere with Hemostasis (antiplatelet agents and anticoagulants)
Clinical Impact:	The concurrent use of an antiplatelet agent or anticoagulant with sertraline hydrochloride may potentiate the risk of bleeding.
Intervention:	Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [See Warnings and Precautions (5.3)].
Examples:	aspirin, clopidogrel, heparin, warfarin
Drugs Highly Bound to Plasma Protein
Clinical Impact:	Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of sertraline hydrochloride with another drug that is highly bound to plasma protein may increase free concentrations of sertraline hydrochloride or other tightly-bound drugs in plasma [See Clinical Pharmacology (12.3)].
Intervention:	Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs as warranted.
Examples:	warfarin
Drugs Metabolized by CYP2D6
Clinical Impact:	Sertraline hydrochloride is a CYP2D6 inhibitor [See Clinical Pharmacology (12.3)]. The concomitant use of sertraline hydrochloride with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate.
Intervention:	Decrease the dosage of a CYP2D6 substrate if needed with concomitant sertraline hydrochloride use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride is discontinued.
Examples:	propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine
Phenytoin
Clinical Impact:	Phenytoin is a narrow therapeutic index drug. Sertraline hydrochloride may increase phenytoin concentrations.
Intervention:	Monitor phenytoin levels when initiating or titrating sertraline hydrochloride. Reduce phenytoin dosage if needed.
Examples:	phenytoin, fosphenytoin

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
Drug Name	Effect on Concentration of Nevirapine or Concomitant Drug	Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir*	↓ Atazanavir ↑ Nevirapine	Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir* Fosamprenavir/Ritonavir*	↓Amprenavir ↑Nevirapine ↓Amprenavir ↑Nevirapine	Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir*	↓ Indinavir	The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir*	↓ Lopinavir	Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra^® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir*	↓Nelfinavir M8 Metabolite ↓Nelfinavir C_min	The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/ritonavir	The interaction between nevirapine and saquinavir/ritonavir has not been evaluated	The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz* Delavirdine Etravirine Rilpivirine	↓Efavirenz	The appropriate doses of these combinations with respect to safety and efficacy have not been established. Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.
Hepatitis C Antiviral Agents
Boceprevir	Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine.	Nevirapine and boceprevir should not be coadministered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy.
Telaprevir	Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir.	Nevirapine and telaprevir should not be coadministered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events.
Other Agents
Analgesics: Methadone*	↓Methadone	Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics: Amiodarone, disopyramide, lidocaine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Antibiotics: Clarithromycin* Rifabutin* Rifampin*	↓Clarithromycin ↑14-OH clarithromycin ↑Rifabutin ↓ Nevirapine	Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium aviumintracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered. Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants: Carbamazepine, clonazepam, ethosuximide	Plasma concentrations of nevirapine and the anticonvulsant may be decreased.	Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals: Fluconazole* Ketoconazole* Itraconazole	↑Nevirapine ↓ Ketoconazole ↓ Itraconazole	Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events. Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics: Warfarin	Plasma concentrations may be increased.	Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers: Diltiazem, nifedipine, verapamil	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Cancer chemotherapy: Cyclophosphamide	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Ergot alkaloids: Ergotamine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Motility agents: Cisapride	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Opiate agonists: Fentanyl	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Oral contraceptives: Ethinyl estradiol and Norethindrone*	↓ Ethinyl estradiol ↓ Norethindrone	Despite lower ethinyl estradiol and norethindrone exposures when coadministered with nevirapine, literature reports suggest that nevirapine has no effect on pregnancy rates among HIV-infected women on combined oral contraceptives. When coadministered with nevirapine, no dose adjustment of ethinyl estradiol or norethindrone is needed when used in combination for contraception. When these oral contraceptives are used for hormonal regulation during nevirapine therapy, the therapeutic effect of the hormonal therapy should be monitored.
* The interaction between nevirapine and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine, danazol	Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem	Do not exceed 40 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (> 1 quart daily)

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Drugs That Interfere with Hemostasis
Clinical Impact:	• Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of Celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of celecoxib with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200 to 400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100 to 325 mg).
Intervention:	Concomitant use of celecoxib and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Celecoxib is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	• During concomitant use of celecoxib and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of celecoxib and ACE-inhibitors or ARBs in patients who are elderly, volume- depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of celecoxib with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact:	The concomitant use of Celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of celecoxib and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of celecoxib and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Celecoxib has no effect on methotrexate pharmacokinetics.
Intervention:	During concomitant use of celecoxib and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of celecoxib and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of celecoxib and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention:	The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of celecoxib and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of celecoxib and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or inducers
Clinical Impact:	Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Coadministration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib.
Intervention:	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [see Clinical Pharmacology (12.3)].
CYP2D6 substrates
Clinical Impact:	In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs.
Intervention:	Evaluate each patient’s medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [see Clinical Pharmacology (12.3)].
Corticosteroids
Clinical Impact:	Concomitant use of corticosteroids with celecoxib may increase the risk of GI ulceration or bleeding.
Intervention:	Monitor patients with concomitant use of celecoxib with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)].

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Table 3 Includes clinically significant drug interactions with buprenorphine and naloxone sublingual tablets
Benzodiazepines
Clinical Impact:	There have been a number of reports regarding coma and death associated with the misuse and abuse of the combination of buprenorphine and benzodiazepines. In many, but not all of these cases, buprenorphine was misused by self-injection of crushed buprenorphine tablets. Preclinical studies have shown that the combination of benzodiazepines and buprenorphine altered the usual ceiling effect on buprenorphine-induced respiratory depression, making the respiratory effects of buprenorphine appear similar to those of full opioid agonists.
Intervention:	Closely monitor patients with concurrent use of buprenorphine and naloxone sublingual tablets and benzodiazepines. Warn patients that it is extremely dangerous to self-administer benzodiazepines while taking buprenorphine and naloxone sublingual tablets, and warn patients to use benzodiazepines concurrently with buprenorphine and naloxone sublingual tablets only as directed by their healthcare provider.
Non-Benzodiazepine Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effects, the concomitant use of non-benzodiazepine CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.2, 5.3)].
Examples:	Alcohol, non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids.
Inhibitors of CYP3A4
Clinical Impact:	The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of buprenorphine and naloxone sublingual tablets is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease [see Clinical Pharmacology (12.3)], potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to buprenorphine.
Intervention:	If concomitant use is necessary, consider dosage reduction of buprenorphine and naloxone sublingual tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the buprenorphine and naloxone sublingual tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples:	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact:	The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine [see Clinical Pharmacology (12.3)], potentially resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both therapeutic effects and adverse reactions and may cause serious respiratory depression.
Intervention:	If concomitant use is necessary, consider increasing the buprenorphine and naloxone sublingual tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider buprenorphine and naloxone sublingual tablets dosage reduction and monitor for signs of respiratory depression.
Examples:	Rifampin, carbamazepine, phenytoin
Antiretrovirals: Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Clinical Impact:	Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine, and etravirine are known CYP3A inducers, whereas delaviridine is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects.
Intervention:	Patients who are on chronic buprenorphine and naloxone sublingual tablets treatment should have their dose monitored if NNRTIs are added to their treatment regimen.
Examples:	efavirenz, nevirapine, etravirine, delavirdine
Antiretrovirals: Protease inhibitors (PIs)
Clinical Impact:	Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity (atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine, and patients in one study reported increased sedation. Symptoms of opioid excess have been found in postmarketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly.
Intervention:	Monitor patients taking buprenorphine and naloxone sublingual tablets and atazanavir with and without ritonavir, and reduce dose of buprenorphine and naloxone sublingual tablets if warranted.
Examples:	atazanavir, ritonavir
Antiretrovirals: Nucleoside reverse transcriptase inhibitors (NRTIs)
Clinical Impact:	Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected.
Intervention:	None
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue buprenorphine and naloxone sublingual tablets if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).
Intervention:	The use of buprenorphine and naloxone sublingual tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Muscle Relaxants
Clinical Impact:	Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients receiving muscle relaxants and buprenorphine and naloxone sublingual tablets for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of buprenorphine and naloxone sublingual tablets and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when buprenorphine and naloxone sublingual tablets are used concomitantly with anticholinergic drugs.

Table name:

^aDrugs That May Decrease Tacrolimus Blood Concentrations
a) This table is not all inclusive.
Anticonvulsants	Antimicrobials
carbamazepine	rifabutin
phenobarbital	caspofungin
phenytoin	rifampin
Herbal Preparations	Other Drugs
St. John’s Wort	sirolimus

Table name:

Interacting Drug	Interaction
Antacids, sucralfate, multivitamins, and other products containing multivalent cations	Moxifloxacin absorption is decreased. Administer AVELOX Tablet at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3, 17.2)
Warfarin	Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. (6.4, 7.2, 12.3)
Class IA and Class III antiarrhythmics:	Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.3, 7.4)

Table name:

Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
	? CBZ epoxide	May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

Table name:

blood dyscrasias -
seeCONTRAINDICATIONS
cancer
collagen vascular disease
congestive heart failure

diarrhea
elevated temperature
hepatic disorders
infectious hepatitis
jaundice

hyperthyroidism
poor nutritional state
steatorrhea
vitamin K deficiency

Table name:

blood dyscrasias - see cancer collagen vascular disease congestive heart failure
CONTRAINDICATIONS

diarrhea elevated temperature hepatic disorders infectious hepatitis jaundice

hyperthyroidism poor nutritional state steatorrhea vitamin K deficiency

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including: antacids, sucralfate, multivitamins	Decreased AVELOX absorption. Take AVELOX Tablet at least 4 hours before or 8 hours after these products. ( 2.2 , 7.1 , 12.3 )
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time/INR, and bleeding. ( 6 , 7.2 , 12.3 )
Class IA and Class III antiarrhythmics:	Proarrhythmic effect may be enhanced. Avoid concomitant use. ( 5.6 , 7.5 )
Antidiabetic agents	Carefully monitor blood glucose. ( 5.11 , 7.3 )

Table name:

Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.6).]
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported . Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [see Adverse Reactions (6.1).]
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution 2-fold increase in exposure	Monitor for sildenafil toxicity (see Pharmacokinetics -(12.3)-] .
Duloxetine	Avoid Use 5-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx ^® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2)].	Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

Table name:

Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug Name	Effect on Concentration of Lopinavir or Concomitant Drug	Clinical Comments
HIV-1 Antiviral Agents
HIV-1 Protease Inhibitor: fosamprenavir/ritonavir	↓ amprenavir ↓ lopinavir	An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: indinavir*	↑ indinavir	Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily [see Clinical Pharmacology ( 12.3)] . KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor: nelfinavir*	↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir	KALETRA should not be administered once daily in combination with nelfinavir [see Dosage and Administration ( 2) and Clinical Pharmacology ( 12.3)] .
HIV-1 Protease Inhibitor: ritonavir*	↑ lopinavir	Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: saquinavir*	↑ saquinavir	The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor: tipranavir	↓ lopinavir AUC and C _min	KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily).
HIV CCR5 – Antagonist: maraviroc	↑ maraviroc	Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry ^® (maraviroc).
Non-nucleoside Reverse Transcriptase Inhibitor: etravirine	↓ etravirine	Because the reduction in the mean systemic exposures of etravirine in the presence of lopinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, no dose adjustment is required.
Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz, nevirapine	↓ lopinavir	KALETRA dose increase is recommended in all patients [see Dosage and Administration ( 2) and Clinical Pharmacology ( 12.3)] . Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz. Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz. KALETRA should not be administered once daily in combination with efavirenz or nevirapine [see Dosage and Administration ( 2) and Clinical Pharmacology ( 12.3)] .
Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine	↑ lopinavir	Appropriate doses of the combination with respect to safety and efficacy have not been established.
Non-nucleoside Reverse Transcriptase Inhibitor: rilpivirine	↑ rilpivirine	No dose adjustment is required.
Nucleoside Reverse Transcriptase Inhibitor: didanosine		KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).
Nucleoside Reverse Transcriptase Inhibitor: tenofovir	↑ tenofovir	KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitors: abacavir zidovudine	↓ abacavir ↓ zidovudine	KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.
Other Agents
Antiarrhythmics e.g.: amiodarone, bepridil, lidocaine (systemic), quinidine	↑ antiarrhythmics	Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.
Anticancer Agents: vincristine, vinblastine, dasatinib, nilotinib	↑ anticancer agents	Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents. For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.
Anticoagulants: warfarin, rivaroxaban	↑ rivaroxaban	Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored. Avoid concomitant use of rivaroxaban and KALETRA. Co-administration of KALETRA and rivaroxaban is expected to result in increased exposure of rivaroxaban which may lead to risk of increased bleeding.
Anticonvulsants: carbamazepine, phenobarbital, phenytoin	↓ lopinavir ↓ phenytoin	KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
Anticonvulsants: lamotrigine, valproate	↓ lamotrigine ↓ or ↔ valproate	Co-administration of KALETRA and lamotrigine or valproate may decrease the exposure of lamotrigine or valproate. A dose increase of lamotrigine or valproate may be needed when co-administered with KALETRA and therapeutic concentration monitoring for lamotrigine may be indicated; particularly during dosage adjustments.
Antidepressant: bupropion	↓ bupropion ↓ active metabolite, hydroxybupropion	Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant: trazodone	↑ trazodone	Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-infective: clarithromycin	↑ clarithromycin	For patients with renal impairment, the following dosage adjustments should be considered: For patients with CL _CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CL _CR < 30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary.
Antifungals: ketoconazole*, itraconazole, voriconazole	↑ ketoconazole ↑ itraconazole ↓ voriconazole	High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended. Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients.
Anti-gout: colchicine	↑ colchicine	Patients with renal or hepatic impairment should not be given colchicine with KALETRA. Treatment of gout flares-co-administration of colchicine in patients on KALETRA: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on KALETRA: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial: bedaquiline	↑ bedaquiline	Bedaquiline should only be used with KALETRA if the benefit of co-administration outweighs the risk [see Pharmacokinetics ( 12.3)] .
Antimycobacterial: rifabutin*	↑ rifabutin and rifabutin metabolite	Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antimycobacterial: rifampin	↓ lopinavir	May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone [see Clinical Pharmacology ( 12.3) for magnitude of interaction ].
Antiparasitic: atovaquone	↓ atovaquone	Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Antipsychotics: quetiapine	↑ quetiapine	Initiation of KALETRA in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking KALETRA: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
Benzodiazepines: parenterally administered midazolam	↑ midazolam	Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam [see Contraindications ( 4)] . If KALETRA is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Contraceptive: ethinyl estradiol*	↓ ethinyl estradiol	Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.
Corticosteroids (systemic): e.g. budesonide, dexamethasone, prednisone	↓ lopinavir ↑ glucocorticoids	Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly. Concomitant use may result in increased steroid concentrations and reduced serum cortisol concentrations. Concomitant use of glucocorticoids that are metabolized by CYP3A, particularly for long-term use, should consider the potential benefit of treatment versus the risk of systemic corticosteroid effects. Concomitant use may increase the risk for development of systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression.
Dihydropyridine Calcium Channel Blockers: e.g. felodipine, nifedipine, nicardipine	↑ dihydropyridine calcium channel blockers	Caution is warranted and clinical monitoring of patients is recommended.
Disulfiram/metronidazole		KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Endothelin Receptor Antagonists: bosentan	↑ bosentan	Co-administration of bosentan in patients on KALETRA: In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Co-administration of KALETRA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA. After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HCV-Protease Inhibitor: boceprevir	↓ lopinavir ↓ boceprevir ↓ ritonavir	It is not recommended to co-administer KALETRA and boceprevir. Concomitant administration of KALETRA and boceprevir reduced boceprevir, lopinavir and ritonavir steady-state exposures [see Clinical Pharmacology ( 12.3)] .
HCV-Protease Inhibitor: simeprevir	↑ simeprevir	It is not recommended to co-administer KALETRA and simeprevir.
HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin	↑ atorvastatin ↑ rosuvastatin	Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day. See Drugs with No Observed or Predicted Interactions with KALETRA ( 7.4) and Clinical Pharmacology ( 12.3) for drug interaction data with other HMG-CoA reductase inhibitors.
Immunosuppressants: e.g. cyclosporine, tacrolimus, sirolimus	↑ immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Inhaled or Intranasal Steroids e.g.: fluticasone, budesonide	↑ glucocorticoids	Concomitant use of KALETRA and fluticasone or other glucocorticoids that are metabolized by CYP3A is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. Concomitant use may result in increased steroid concentrations and reduce serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during postmarketing use in patients when certain ritonavir-containing products have been co-administered with fluticasone propionate or budesonide.
Long-acting beta-adrenoceptor Agonist: salmeterol	↑ salmeterol	Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesics: methadone,* fentanyl	↓ methadone ↑ fentanyl	Dosage of methadone may need to be increased when co-administered with KALETRA. Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA.
PDE5 inhibitors: avanafil, sildenafil, tadalafil, vardenafil	↑ avanafil ↑ sildenafil ↑ tadalafil ↑ vardenafil	Do not use KALETRA with avanafil because a safe and effective avanafil dosage regimen has not been established. Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio ^®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA [see Contraindications ( 4)] . The following dose adjustments are recommended for use of tadalafil (Adcirca ^®) with KALETRA: Co-administration of ADCIRCA in patients on KALETRA: In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Co-administration of KALETRA in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: It is recommended not to exceed the following doses: • Sildenafil: 25 mg every 48 hours • Tadalafil: 10 mg every 72 hours • Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events.
* see Clinical Pharmacology ( 12.3) for magnitude of interaction.

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Factors	Dosage Adjustment of aripiprazole
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors	Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double usual dose over 1 to 2 weeks

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AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NCor25%increase^a	48%decrease
Carbamazepine(CBZ)	NC	40%decrease
CBZepoxide^b	NC	NE
Valproic acid	11%decrease	14%decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NCatTPM dosesupto400 mg/day	13%decrease

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DRUG	DESCRIPTION OF INTERACTION
Corticosteroids	Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents	Increases plasma salicylate level.
Alkalizing Agents	Decreased plasma salicylate levels.

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Table 4. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin	Monitor phenytoin level (7)
Methotrexate	Monitor for methotrexate toxicity (7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin tablets absorption. Take 2 hours before or 6 hours after ciprofloxacin tablets (7)

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DRUG	DESCRIPTION OF INTERACTION
Corticosteroids	Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents	Increases plasma salicylate level.
Alkalinizing Agents	Decreased plasma salicylate levels.

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Table 4. Other Potentially Significant Drug Interactions
Concomitant Drug Class or Food	Noted or Anticipated Outcome	Clinical Comment
HMG-Co A Reductase Inhibitors: atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin	Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality) P-gp substrate; rhabdomyolysis has been reported	Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy.
Other Lipid-Lowering Drugs: fibrates, gemfibrozil
Digitalis Glycosides: digoxin

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Antibiotics	Antineoplastic	Antifungals	Anti-Inflammatory Drugs	Gastrointestinal Agents	Immunosuppressives	Other Drugs
ciprofloxacin	melphalan	amphotericin B	azapropazon	cimetidine	tacrolimus	fibric acid derivatives (e.g., bezafibrate, fenofibrate)
gentamicin		ketoconazole	colchicine	ranitidine		methotrexate
tobramycin			diclofenac
trimethoprim with sulfamethoxazole			naproxen
vancomycin			sulindac

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Table 3Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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I. Due to the competition of salicylate with other drugs for binding to serum albumin the following drug interactions may occur:
DRUG	DESCRIPTION OF INTERACTION
Sulfonylureas	Hypoglycemia potentiated.
Methotrexate	Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants	Increased bleeding.
II. Drugs changing salicylate levels by altering renal tubular reabsorption:
DRUG	DESCRIPTION OF INTERACTION
Corticosteroids	Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents	Increases plasma salicylate levels.
Alkanizing Agents	Decreased plasma salicylate levels.
III. Drugs with complicated interactions with salicylates:
DRUG	DESCRIPTION OF INTERACTION
Heparin	Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients.
Pyrazinamide	Inhibits pyrazinamide-induced hyperuricemia.
Uricosuric Agents	Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.
The following alterations of laboratory tests have been reported during salicylate therapy:
LABORATORY TESTS	EFFECT OF SALICYLATES
Thyroid Function	Decreased PBI; increased t₃ uptake.
Urinary Sugar	False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.).
5-Hydroxyindole acetic acid	False negative with fluorometric test.
Acetone ketone bodies	False positive FeCI₃ in Gerhardt reaction; red color persists with boiling.
17-OH corticosteroids	False reduced values with >4.8g q.d. salicylate.
Vanilmandelic acid	False reduced values.
Uric Acid	May increase or decrease depending on dose.
Prothrombin	Decreased levels; slightly increased prothrombin time.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. ₄ ₃
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT , is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. ₄ ₄ ₄ ₄ ₃ ₄ ₄ ₄
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. ₄
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T to T , leading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T and T levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). ₄ ₃ ₃ ₄ ₃ ₄ ₃ ₄ ₃ ₄
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of I, I, and Tc. ¹²³ ¹³¹ ^99m
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 3Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Table 5: Effects on Steady-State Fexofenadine Pharmacokinetics After 7 Days of Coadministration With Fexofenadine Hydrochloride 120 mg Every 12 Hours in Healthy Adult Subjects (n = 24)
Concomitant Drug	C_maxSS (Peak plasma concentration)	AUC_ss(0-12h) (Extent of systemic exposure)
Erythromycin (500 mg every 8 hrs)	+82%	+109%
Ketoconazole (400 mg once daily)	+135%	+164%

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AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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blood dyscrasias -
seeCONTRAINDICATIONS
cancer
collagen vascular disease
congestive heart failure

diarrhea
elevated temperature
hepatic disorders
infectious hepatitis
jaundice

hyperthyroidism
poor nutritional state
steatorrhea
vitamin K deficiency

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Table 3: Established and Other Potentially Significant Drug Interactions: Alteration in CERDELGA Dosage May Be Recommended Based on Drug Interaction Studies or on Predicted Interaction in EMs and IMs
	Recommended CERDELGA Dosage, by CYP2D6 Metabolizer Status
CYP450 Inhibitors	EM	IM
Strong or Moderate CYP2D6 inhibitors concomitantly with Strong or Moderate CYP3A inhibitors	Contraindicated	Contraindicated
Strong CYP2D6 inhibitors e.g., paroxetine	84 mg once daily	84 mg once daily
Moderate CYP2D6 inhibitors e.g., terbinafine	84 mg once daily	84 mg once daily
Strong CYP3A inhibitors e.g., ketoconazole	84 mg once daily	Contraindicated
Moderate CYP3A inhibitors e.g., fluconazole	84 mg once daily	Not recommended

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine (CBZ) and CBZ epoxide	? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2 fold.
Valproate	? valproate	Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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CYP2C19 or CYP3A4 Inducers
Clinical Impact:	Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology ( 12.3)] .
Intervention:	St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions ( 5.9)] . Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:	Increased exposure of omeprazole [see Clinical Pharmacology ( 12.3)] .
Intervention:	Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole.

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Antiarrhythmics	Dofetilide	Concomitant administration with digoxin was associated with a higher rate of torsades de pointes.
	Moricizine	Reported to increase PR interval and QRS duration. There are reports of first degree atrioventricular block or bundle branch block developing with digitalis administration. The known effects of moricizine on calcium conductance may explain the effects on atrioventricular node conduction.
	Sotalol	Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
Parathyroid Hormone Analog	Teriparatide	Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid Supplement	Thyroid	Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics	Epinepherine	Can increase the risk of cardiac arrhythmias.
	Norepinephrine
	Dopamine
Neuromuscular Blocking Agents	Succinylcholine	May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements	Calcium	If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers	Additive effects on AV node conduction can result in complete heart block.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄ . Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³ I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name:

Drugs That Interfere with Hemostasis
Clinical Impact:	• Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	• During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

Table name:

Calcium Channel Blockers	Antifungals	Antibiotics	Glucocorticoids	Other Drugs
diltiazem	fluconazole	azithromycin	methylprednisolone	allopurinol
nicardipine	itraconazole	clarithromycin		amiodarone
verapamil	ketoconazole	erythromycin		bromocriptine
		quinupristin/		colchicine
	voriconazole	dalfopristin		danazol
				imatinib
				metoclopramide
				nefazodone
				oral contraceptives

Table name:

Drugs That Interfere with Hemostasis
Clinical Impact:		• Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • S er otonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:		Monitor patients with concomitant use of VOLTAREN^® GEL with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact:		Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention:		Concomitant use of VOLTAREN^® GEL and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. VOLTAREN^® GEL is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:		• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or betablockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:		• During concomitant use of VOLTAREN^® GEL and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of VOLTAREN^® GEL and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. •When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:		Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:		During concomitant use of VOLTAREN^® GEL with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact:		The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:		During concomitant use of VOLTAREN^® GEL and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:		NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:		During concomitant use of VOLTAREN^® GEL and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:		Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:		During concomitant use of VOLTAREN^® GEL and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:		Concomitant use of VOLTAREN^® GEL and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention:		During concomitant use of VOLTAREN^® GEL and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:		Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention:		The concomitant use of diclofenac with other NSAIDs or salicylates is notrecommended.
Pemetrexed
Clinical Impact:		Concomitant use of VOLTAREN^® GEL and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:		During concomitant use of VOLTAREN^® GEL and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and Gl toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.

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Drug interaction Associated with increased Risk of Myopathy/Rhabdomyolysis (2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
*For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily*
Grapefruit juice	Avoid grapefruit juice

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Inhibitors of CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6
Clinical Impact:	Methadone undergoes hepatic N-demethylation by several cytochrome P450 (CYP) isoforms, including CYP3A4, CYP2B6, CYP2C19, CYP2C9, and CYP2D6. The concomitant use of methadone hydrochloride tablets and CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors can increase the plasma concentration of methadone, resulting in increased or prolonged opioid effects, and may result in a fatal overdose, particularly when an inhibitor is added after a stable dose of methadone hydrochloride tablets is achieved. These effects may be more pronounced with concomitant use of drugs that inhibit more than one of the CYP enzymes listed above. After stopping a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitor, as the effects of the inhibitor decline, the methadone plasma concentration can decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or withdrawal symptoms in patients physically dependent on methadone.
Intervention:	If concomitant use is necessary, consider dosage reduction of methadone hydrochloride tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitor is discontinued, follow patients for signs of opioid withdrawal and consider increasing the methadone hydrochloride tablets dosage until stable drug effects are achieved.
Examples:	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir), fluconazole, fluvoxamine, some selective serotonin reuptake inhibitors (SSRIs) (e.g., sertraline, fluvoxamine)
Inducers of CYP3A4, CYP2B6, CYP2C19, or CYP2C9
Clinical Impact:	The concomitant use of methadone hydrochloride tablets and CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers can decrease the plasma concentration of methadone [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of withdrawal symptoms in patients physically dependent on methadone. These effects could be more pronounced with concomitant use of drugs that can induce multiple CYP enzymes. After stopping a CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducer, as the effects of the inducer decline, the methadone plasma concentration can increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression, sedation, or death.
Intervention:	If concomitant use is necessary, consider increasing the methadone hydrochloride tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducer is discontinued, consider methadone hydrochloride tablets dosage reduction and monitor for signs of respiratory depression and sedation.
Examples:	Rifampin, carbamazepine, phenytoin, St. John’s Wort, Phenobarbital
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.6)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Potentially Arrhythmogenic Agents
Clinical Impact:	Pharmacodynamic interactions may occur with concomitant use of methadone and potentially arrhythmogenic agents or drugs capable of inducing electrolyte disturbances (hypomagnesemia, hypokalemia).
Intervention:	Monitor patients closely for cardiac conduction changes.
Examples:	Drugs known to have potential to prolong QT interval: Class I and III antiarrhythmics, some neuroleptics and tricyclic antidepressants, and calcium channel blockers. Drugs capable of inducing electrolyte disturbances: Diuretics, laxatives, and, in rare cases, mineralocortocoid hormones.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions (5.8)].
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue methadone hydrochloride tablets if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.8)] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
Intervention:	The use of methadone hydrochloride tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of methadone hydrochloride tablets and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Methadone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of methadone hydrochloride tablets and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when methadone hydrochloride tablets are used concomitantly with anticholinergic drugs.

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Table 15: Clinically Important Drug Interactions with Aripiprazole Tablets:
Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of aripiprazole tablets with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole tablets compared to the use of aripiprazole tablets alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole tablets with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole tablets dosage[see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of aripiprazole tablets and carbamazepine decreased the exposure of aripiprazole tablets compared to the use of aripiprazole tablets alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole tablets with a strong CYP3A4 inducer, consider increasing the aripiprazole tablets dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole tablets has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.7)].
Benzodiazepines (e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone.The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.7)]	Monitor sedation and blood pressure. Adjust dose accordingly.

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol,	famotidine	nizatidine
systemic and inhaled	felodipine	norfloxacin
amoxicillin	finasteride	ofloxacin
ampicillin,	hydrocortisone	omeprazole
with or without	isoflurane	prednisone, prednisolone
sulbactam	isoniazid	ranitidine
atenolol	isradipine	rifabutin
azithromycin	influenza vaccine	roxithromycin
caffeine,	ketoconazole	sorbitol
dietary ingestion	lomefloxacin	(purgative doses do not
cefaclor	mebendazole	inhibit theophylline
co-trimoxazole	medroxyprogesterone	absorption)
(trimethoprim and	methylprednisolone	sucralfate
sulfamethoxazole)	metronidazole	terbutaline, systemic
diltiazem	metoprolol	terfenadine
dirithromycin	nadolol	tetracycline
enflurane	nifedipine	tocainide

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 13. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Table 8: Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C_max and AUC_τ)	Recommendations for Drug Dosage Adjustment/Comments
SirolimusResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (400 mg q24h)Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	Contraindicated

Efavirenz (300 mg q24h) (CYP3A4 Inhibition)	Slight Increase in AUC_τ	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)(CYP3A4 Inhibition)	No Significant Effect of Voriconazole on Ritonavir C_max or AUC_τ	Contraindicated because of significant reduction of voriconazole C_max and AUC_τ

Low-dose Ritonavir (100 mg q12h)	Slight Decrease in Ritonavir C_max and AUC_τ	Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole C_max and AUC_τ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated
Cyclosporine (CYP3A4 Inhibition)	AUC_τ Significantly Increased; No Significant Effect on C_max	When initiating therapy with VFEND in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
MethadoneResults based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30–100 mg q24h) (CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7)]
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see Drug Interactions (7)].
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7)].
NSAIDsNon-Steroidal Anti-Inflammatory Drug including. ibuprofen and diclofenac (CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [see Drug Interactions (7)].
Tacrolimus (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)	Increased	Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects on Indinavir Exposure	No dosage adjustment for indinavir when coadministered with VFEND

	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.
Everolimus (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Concomitant administration of voriconazole and everolimus is not recommended.

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
* Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol,	diltiazem	medroxyprogesterone	roxithromycin
systemic and inhaled	dirithromycin	methylprednisolone	sorbitol
amoxicillin	enflurane	metronidazole	(purgative doses
ampicillin,	famotidine	metoprolol	do not inhibit
with or without	felodipine	nadolol	theophylline
sulbactam	finasteride	nifedipine	absorption)
atenolol	hydrocortisone	nizatidine	sucralfate
azithromycin	isoflurane	norfloxacin	terbutaline, systemic
caffeine,	isoniazid	ofloxacin	terfenadine
dietary ingestion	isradipine	omeprazole	tetracycline
cefaclor	influenza vaccine	prednisone,	tocainide
co-trimoxazole	ketoconazole	prednisolone
(trimethoprim and	lomefloxacin	ranitidine
sulfamethoxazole)	mebendazole	rifabutin

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. ₄ ₃
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT , is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. ₄ ₄ ₄ ₄ ₃ ₄ ₄ ₄
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. ₄
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T to T , leading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T and T levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). ₄ ₃ ₃ ₄ ₃ ₄ ₃ ₄ ₃ ₄
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of I, I, and Tc. ¹²³ ¹³¹ ^99m
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 11 Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies (see CLINICAL PHARMACOLOGY, for Magnitude of Interaction, Tables 6 and 7)
Concomitant Drug Class: Drug Name	Effect on Concentration	Clinical Comment
HIV-Antiviral Agents
Non-nucleoside Reverse Transcriptase Inhibitors:		Appropriate doses for these combinations, with respect to safety and efficacy, have not been established.
delavirdine	↑ nelfinavir ↓ delavirdine
nevirapine	↓ nelfinavir (C_min)
Nucleoside Reverse Transcriptase Inhibitor: didanosine		It is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after VIRACEPT (given with food).
Protease Inhibitors:		Appropriate doses for these combinations, with respect to safety and efficacy, have not been established.
indinavir	↑ nelfinavir ↑ indinavir
ritonavir	↑ nelfinavir
saquinavir	↑ saquinavir
Other Agents
Anti-coagulant: warfarin	warfarin	Coadministration of warfarin and VIRACEPT may affect concentrations of warfarin. It is recommended that the INR (international normalized ratio) be monitored carefully during treatment with VIRACEPT, especially when commencing therapy.
Anti-convulsants:		May decrease nelfinavir plasma concentrations. VIRACEPT may not be effective due to decreased nelfinavir plasma concentrations in patients taking these agents concomitantly.
carbamazepine phenobarbital	↓ nelfinavir
Anti-convulsant:		Phenytoin plasma/serum concentrations should be monitored; phenytoin dose may require adjustment to compensate for altered phenytoin concentration.
phenytoin	↓ phenytoin
Anti-depressant: trazodone	↑ trazodone	Concomitant use of trazodone and VIRACEPT may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as VIRACEPT, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-gout colchicine	↑ colchicine	Treatment of gout flares– coadministration of colchicine in patients on VIRACEPT: 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout-flares– coadministration of colchicine in patients on VIRACEPT: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF)– coadministration of colchicine in patients on VIRACEPT: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Patients with renal or hepatic impairment should not be given colchicine with VIRACEPT.
Anti-Mycobacterial:		It is recommended that the dose of rifabutin be reduced to one-half the usual dose when administered with VIRACEPT; 1250 mg BID is the preferred dose of VIRACEPT when coadministered with rifabutin.
rifabutin	↑ rifabutin ↓ nelfinavir (750 mg TID) ↔ nelfinavir (1250 mg BID)
Endothelin receptor antagonists: bosentan	↑ bosentan	Coadministration of bosentan in patients on VIRACEPT or coadministration of VIRACEPT in patients on bosentan: Start at or adjust bosentan to 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitor:		Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with VIRACEPT.
atorvastatin	↑ atorvastatin
rosuvastatin	↑ rosuvastatin
Immuno-suppressants:		Plasma concentrations may be increased by VIRACEPT.
cyclosporine tacrolimus sirolimus	↑ immuno-suppressants	Plasma concentrations may be increased by VIRACEPT.
Inhaled beta agonist: salmeterol	↑ salmeterol	Concurrent administration of salmeterol with VIRACEPT is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Inhaled/nasal steroid: Fluticasone	↑ fluticasone	Concomitant use of fluticasone propionate and VIRACEPT may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use.
Macrolide Antibiotic: azithromycin	↑ azithromycin	Dose adjustment of azithromycin is not recommended, but close monitoring for known side effects such as liver enzyme abnormalities and hearing impairment is warranted.
Narcotic Analgesic:		Dosage of methadone may need to be increased when coadministered with VIRACEPT.
methadone	↓ methadone
Oral Contraceptive:		Alternative or additional contraceptive measures should be used when oral contraceptives and VIRACEPT are coadministered.
ethinyl estradiol	↓ ethinyl estradiol
PDE5 Inhibitors: sildenafil vardenafil tadalafil	↑ PDE5 Inhibitors	Concomitant use of PDE5 inhibitors and VIRACEPT should be undertaken with caution. May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Use of sildenafil (REVATIO) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications]. The following dose adjustments are recommended for use of tadalafil (ADCIRCA™) with VIRACEPT: Coadministration of ADCIRCA in patients on VIRACEPT or coadministration of VIRACEPT in patients on ADCIRCA: Start at or adjust ADCIRCA to 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 24 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours, is recommended. Use with increased monitoring for adverse events.

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Drugs That Interfere with Hemostasis
Clinical Impact:	Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of celecoxib with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions ( 5.11 ) ].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions ( 5.2 ) ]. In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200 to 400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100 to 325 mg).
Intervention:	Concomitant use of celecoxib and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions ( 5.11 ) ]. Celecoxib is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of celecoxib and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of celecoxib and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions ( 5.6 ) ]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as postmarketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of celecoxib with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see Warnings and Precautions ( 5.6 ) ].
Digoxin
Clinical Impact:	The concomitant use of Celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of celecoxib and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of celecoxib and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Celecoxib has no effect on methotrexate pharmacokinetics.
Intervention:	During concomitant use of celecoxib and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of celecoxib and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of celecoxib and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions ( 5.2 ) ].
Intervention:	The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of celecoxib and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of celecoxib and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or inducers
Clinical Impact:	Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Coadministration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas coadministration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib.
Intervention:	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers [ see Clinical Pharmacology ( 12.3 ) ].
CYP2D6 substrates
Clinical Impact:	In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs.
Intervention:	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates [ see Clinical Pharmacology ( 12.3 ) ].
Corticosteroids
Clinical Impact:	Concomitant use of corticosteroids with celecoxib may increase the risk of GI ulceration or bleeding.
Intervention:	Monitor patients with concomitant use of celecoxib with corticosteroids for signs of bleeding [ see Warnings and Precautions ( 5.2 ) ].

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Inhibitors of CYP3A4
Clinical Impact:	The concomitant use of Fentanyl Citrate Injection and CYP3A4 inhibitors can increase the plasma concentration of fentanyl, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of Fentanyl Citrate Injection is achieved [see Warnings and Precautions (5.3)].After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to fentanyl.
Intervention:	If concomitant use is necessary, consider dosage reduction of Fentanyl Citrate Injection until stable drug effects are achieved [see Dosage and Administration (2.1)]. Monitor patients for respiratory depression and sedation at frequent intervals.If a CYP3A4 inhibitor is discontinued, consider increasing the Fentanyl Citrate Injection dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples:	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir), grapefruit juice.
CYP3A4 Inducers
Clinical Impact:	The concomitant use of Fentanyl Citrate Injection and CYP3A4 inducers can decrease the plasma concentration of fentanyl [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to fentanyl [see Warnings and Precautions (5.3)]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention:	If concomitant use is necessary, consider increasing the Fentanyl Citrate Injection dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider Fentanyl Citrate Injection dosage reduction and monitor for signs of respiratory depression.
Examples:	Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	The concomitant use of Fentanyl Citrate Injection with CNS depressants my result in decreased pulmonary artery pressure and may cause hypotension. Even small dosages of diazepam may cause cardiovascular depression when added to high dose or anesthetic dosages of Fentanyl Citrate Injection. As postoperative analgesia, concomitant use of Fentanyl Citrate Injection can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	As postoperative analgesia, start with a lower dose of Fentanyl Citrate Injection and monitor patients for signs of respiratory depression, sedation, and hypotension. Fluids or other measures to counter hypotension should be available [see Warnings and Precautions (5.4)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, barbiturates, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions (5.7)].
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Fentanyl Citrate Injection if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue)..
Monoamine Oxidase Inhibitors
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.7)] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)]
Intervention:	The use of Fentanyl Citrate Injection is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	Phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of Fentanyl Citrate Injection and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	Butorphanol, nalbuphine, pentazocine, buprenorphine.
Muscle Relaxants
Clinical Impact:	Fentanyl may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when Fentanyl Citrate Injection is used concomitantly with anticholinergic drugs.
Neuroleptics
Clinical Impact:	Elevated blood pressure, with and without pre-existing hypertension, has been reported following administration of Fentanyl Citrate Injection combined with a neuroleptic see Warnings and Precautions (5.13)].
Intervention:	ECG monitoring is indicated when a neuroleptic agent is used in conjunction with Fentanyl Citrate Injection as an anesthetic premedication, for the induction of anesthesia, or as an adjunct in the maintenance of general or regional anesthesia.
Nitrous oxide
Clinical Impact:	Nitrous oxide has been reported to produce cardiovascular depression when given with higher doses of Fentanyl Citrate Injection.
Intervention:	Monitor patients for signs of cardiovascular depression that may be greater than otherwise expected.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Drugs That Interfere with Hemostasis
Clinical Impact:	Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of indomethacin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions ( 5.11 )].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions ( 5.2 ) ].
Intervention:	Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions ( 5.11 )].Indomethacin is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of indomethacin capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.During concomitant use of indomethacin capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions ( 5.6 )].When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.It has been reported that the addition of triamterene to a maintenance schedule of Indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together.Both indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently [ see Warnings and Precautions ( 5.6 )].
Intervention:	Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels. [ see Warnings and Precautions ( 5.6 )].
Digoxin
Clinical Impact:	The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention:	During concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions ( 5.2 )]. Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin [see Clinical Pharmacology ( 12.3 )].In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage.
Intervention:	The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Probenecid
Clinical Impact:	When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased.
Intervention:	During the concomitant use of indomethacin and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments.

Table name:

Drug	Effect
Phenylephrine with prior administration of monoamine oxidase inhibitors (MAOI).	Cardiac pressor response potentiated. May cause acute hypertensive crisis.
Phenylephrine with tricyclic antidepressants.	Pressor response increased.
Phenylephrine with ergot alkaloids.	Excessive rise in blood pressure.
Phenylephrine with bronchodilator sympathomimetic agents and with epinephrine or other sympathomimetics.	Tachycardia or other arrhythmias may occur.
Phenylephrine with prior administration of propranolol or other β-adrenergic blockers.	Cardiostimulating effects blocked.
Phenylephrine with atropine sulfate.	Reflex bradycardia blocked; pressor response enhanced.
Phenylephrine with prior administration of phentolamine or other α-adrenergic blockers.	Pressor response decreased.
Phenylephrine with diet preparations, such as amphetamines or phenylpropanolamine.	Synergistic adrenergic response.

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Table 11 Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies (see CLINICAL PHARMACOLOGY, for Magnitude of Interaction, Tables 6 and 7)
Concomitant Drug Class: Drug Name	Effect on Concentration	Clinical Comment
HIV-Antiviral Agents
Protease Inhibitors:		Appropriate doses for these combinations, with respect to safety and efficacy, have not been established.
indinavir	↑ nelfinavir ↑ indinavir
ritonavir	↑ nelfinavir
saquinavir	↑ saquinavir
Non-nucleoside Reverse Transcriptase Inhibitors:		Appropriate doses for these combinations, with respect to safety and efficacy, have not been established.
delavirdine	↑ nelfinavir ↓ delavirdine
nevirapine	↓ nelfinavir (C_min)
Nucleoside Reverse Transcriptase Inhibitor: didanosine		It is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after VIRACEPT (given with food).
Other Agents
Anti-Convulsants:		May decrease nelfinavir plasma concentrations. VIRACEPT may not be effective due to decreased nelfinavir plasma concentrations in patients taking these agents concomitantly.
carbamazepine phenobarbital	↓ nelfinavir
Anti-Convulsant:		Phenytoin plasma/serum concentrations should be monitored; phenytoin dose may require adjustment to compensate for altered phenytoin concentration.
phenytoin	↓ phenytoin
Anti-Mycobacterial:		It is recommended that the dose of rifabutin be reduced to one-half the usual dose when administered with VIRACEPT; 1250 mg BID is the preferred dose of VIRACEPT when coadministered with rifabutin.
rifabutin	↑ rifabutin ↓ nelfinavir (750 mg TID) ↔ nelfinavir (1250 mg BID)
PDE5 Inhibitors: sildenafil vardenafil tadalafil	↑ PDE5 Inhibitors	Concomitant use of PDE5 inhibitors and VIRACEPT should be undertaken with caution. If concomitant use of PDE5 inhibitors and VIRACEPT is required, sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours, is recommended.

HMG-CoA Reductase Inhibitor:		Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with VIRACEPT.
atorvastatin	↑ atorvastatin
rosuvastatin	↑ rosuvastatin
Immuno-suppressants:		Plasma concentrations may be increased by VIRACEPT.
cyclosporine tacrolimus sirolimus	↑ immuno-suppressants	Plasma concentrations may be increased by VIRACEPT.
Narcotic Analgesic:		Dosage of methadone may need to be increased when coadministered with VIRACEPT.
methadone	↓ methadone
Oral Contraceptive:		Alternative or additional contraceptive measures should be used when oral contraceptives and VIRACEPT are coadministered.
ethinyl estradiol	↓ ethinyl estradiol
Macrolide Antibiotic: azithromycin	↑ azithromycin	Dose adjustment of azithromycin is not recommended, but close monitoring for known side effects such as liver enzyme abnormalities and hearing impairment is warranted.
Inhaled/nasal steroid: Fluticasone	↑ fluticasone	Concomitant use of fluticasone propionate and VIRACEPT may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use.
Antidepressant: trazodone	↑ trazodone	Concomitant use of trazodone and VIRACEPT may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as VIRACEPT, the combination should be used with caution and a lower dose of trazodone should be considered.

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Table 5 Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or on Predicted Interaction with INVIRASE/ritonavir
Concomitant Drug Class: Drug Name	Effect on Concentration of Saquinavir or Concomitant Drug	Clinical Comment
HIV-Antiviral Agents
Non-nucleoside reverse transcriptase inhibitor: DelavirdineINVIRASE/ritonavir interaction has not been evaluated.	↑ Saquinavir Effect on delavirdine is not well established	Appropriate doses of the combination with respect to safety and efficacy have not been established.
Non-nucleoside reverse transcriptase inhibitor: EfavirenzSee CLINICAL PHARMACOLOGY: Pharmacokinetics , Table 2 and Table 3 for magnitude of interactions., nevirapine	↓ Saquinavir ↔ Efavirenz	Appropriate doses of the combination of efavirenz or nevirapine and INVIRASE/ritonavir (1000/100 mg bid) with respect to safety and efficacy have not been established.
HIV protease inhibitor: Atazanavir	INVIRASE/ritonavir ↑ Saquinavir ↑ Ritonavir ↔ Atazanavir	Appropriate dosing recommendations for this combination, with respect to efficacy and safety, have not been established. When 1600 mg INVIRASE/100 mg ritonavir and 300 mg atazanavir were coadministered, plasma concentrations of saquinavir and ritonavir were increased.
HIV protease inhibitor: Indinavir	↑ Saquinavir Effect on indinavir is not well established	Appropriate doses of the combination of indinavir and INVIRASE/ritonavir with respect to safety and efficacy have not been established.
HIV protease inhibitor: Lopinavir/ritonavir (coformulated capsule)	↔ Saquinavir ↔ Lopinavir ↓ Ritonavir	Evidence from several clinical trials indicates that saquinavir concentrations achieved with the saquinavir and lopinavir/ritonavir combination are similar to those achieved following saquinavir/ritonavir 1000/100 mg. The recommended dose for this combination is saquinavir 1000 mg plus lopinavir/ritonavir 400/100 mg bid.
HIV protease inhibitor: Tipranavir/ritonavir	↓ Saquinavir	Combining saquinavir with tipranavir/ritonavir is not recommended.
HIV fusion inhibitor: Enfuvirtide	Saquinavir soft gel capsules/ritonavir ↔ enfuvirtide	No clinically significant interaction was noted from a study in 12 HIV patients who received enfuvirtide concomitantly with saquinavir soft gel capsules/ritonavir 1000/100 mg bid. No dose adjustments are required.
Other Agents
Antiarrhythmics: Lidocaine (systemic)	↑ Antiarrhythmics	Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics given with INVIRASE/ritonavir.
Anticoagulant: Warfarin	↑ Warfarin	Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: Carbamazepine, phenobarbital, phenytoin	↓ Saquinavir Effect on carbamazepine, phenobarbital, and phenytoin is not well established	Use with caution, saquinavir may be less effective due to decreased saquinavir plasma concentrations in patients taking these agents concomitantly.
Anti-infective: Clarithromycin	↑ Saquinavir ↑ Clarithromycin	Appropriate doses of the combination of clarithromycin and INVIRASE/ritonavir with respect to safety and efficacy have not been established. Due to the known effect of ritonavir on clarithromycin concentrations, the following dose adjustments are recommended: For patients with renal impairment, the following dosage adjustments should be considered: For patients with CL_CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CL_CR <30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary.
Antifungal: Ketoconazole, itraconazole	↔ Saquinavir ↔ Ritonavir ↑ Ketoconazole	Appropriate doses of the combination of ketoconazole or itraconazole and INVIRASE/ritonavir with respect to safety and efficacy have not been established. When INVIRASE/ritonavir and ketoconazole are coadministered, plasma concentration of ketoconazole was increased (see Table 2 ). Hence, doses of ketoconazole > 200 mg/day are not recommended.
Antimycobacterial: Rifabutin	↓ Saquinavir ↑ Rifabutin	Appropriate doses of the combination of rifabutin and INVIRASE/ritonavir with respect to safety and efficacy have not been established.
Benzodiazepines: Alprazolam, clorazepate, diazepam, flurazepam	↑ Benzodiazepines	Clinical significance is unknown; however, a decrease in benzodiazepine dose may be needed.
Benzodiazepine : Intravenously administered Midazolam	↑ Midazolam	Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, INVIRASE should not be given with orally administered midazolam [see Contraindications (4)]. If INVIRASE is coadministered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Calcium channel blockers : Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine	↑ Calcium channel blockers	Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid: Dexamethasone	↓ Saquinavir	Use with caution, saquinavir may be less effective due to decreased saquinavir plasma concentrations in patients taking these agents concomitantly.
Digitalis Glycosides: Digoxin	↑ Digoxin Increases in serum digoxin concentration were greater in female subjects as compared to male subjects when digoxin was coadministered with INVIRASE/ritonavir.	Concomitant use of INVIRASE/ritonavir with digoxin results in a significant increase in serum concentrations of digoxin. Caution should be exercised when INVIRASE/ritonavir and digoxin are coadministered; serum digoxin concentrations should be monitored and the dose of digoxin may need to be reduced when coadministered with INVIRASE/ritonavir (see WARNINGS ).
Inhaled/nasal steroid: Fluticasone	INVIRASE/ritonavir ↑ Fluticasone	Concomitant use of fluticasone propionate and INVIRASE/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Coadministration of fluticasone propionate and INVIRASE/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects (see WARNINGS ).
HMG-CoA reductase inhibitors : Atorvastatin, rosuvastatin	↑ Atorvastatin ↑ Rosuvastatin	Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as fluvastatin in combination with Invirase/ritonavir (see WARNINGS ).
Immunosuppressants : Cyclosporine, tacrolimus, rapamycin	↑ Immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with INVIRASE/ritonavir.
Narcotic analgesic: Methadone	↓ Methadone	Dosage of methadone may need to be increased when coadministered with INVIRASE/ritonavir.
Oral contraceptives: Ethinyl estradiol	↓ Ethinyl estradiol	Alternative or additional contraceptive measures should be used when estrogen-based oral contraceptives and INVIRASE/ritonavir are coadministered.
PDE5 inhibitors (phosphodiesterase type 5 inhibitors): Sildenafil, vardenafil, tadalafil	↑ Sildenafil ↔ Saquinavir ↑ Vardenafil ↑ Tadalafil	Use sildenafil with caution at reduced doses of 25 mg every 48 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir. Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir. Use tadalafil with caution at reduced doses of no more than 10 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with INVIRASE/ritonavir.
Antidepressant: Trazodone	↑ Trazodone	Concomitant use of trazodone and INVIRASE/ritonavir may increase plasma concentration of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as INVIRASE/ritonavir, the combination should be used with caution and lower dose of trazodone should be considered.
Tricyclic antidepressants : Amitriptyline, imipramine	↑ Tricyclics	Therapeutic concentration monitoring is recommended for tricyclic antidepressants when coadministered with INVIRASE/ritonavir.
Proton pump inhibitors: Omeprazole	↑ Saquinavir	When INVIRASE/ritonavir is co-administered with omeprazole, saquinavir concentrations are increased significantly. If omeprazole or another proton pump inhibitor is taken concomitantly with INVIRASE/ritonavir, caution is advised and monitoring for potential saquinavir toxicities is recommended, particularly gastrointestinal symptoms, increased triglycerides, and deep vein thrombosis.
Herbal Products: St. John's wort (hypericum perforatum)	↓ Saquinavir	Coadministration may lead to loss of virologic response and possible resistance to INVIRASE or to the class of protease inhibitors (see WARNINGS ).
Garlic Capsules	↓ Saquinavir	Coadministration of garlic capsules and saquinavir is not recommended due to the potential for garlic capsules to induce the metabolism of saquinavir which may result in sub-therapeutic saquinavir concentrations.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( > 1 µg/kg/min); Glucocorticoids (hydrocortisone > 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T ₄ and T ₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT ₄. Continued administration results in a decrease in serum T ₄ and normal FT ₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T ₄ and T ₃ to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT ₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T ₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T ₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5’-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone > 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T ₄ to T ₃, leading to decreased T ₃ levels. However, serum T ₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T ₃ and T ₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T ₃ concentrations by 30% with minimal change in serum T ₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T ₃ and T ₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ⁹⁹mTc
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs that Interfere with Hemostasis
Clinical Impact :	Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention :	Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions ( 5 . 11)].
Aspirin
Clinical Impact :	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions ( 5 . 2)].
Intervention :	Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions ( 5 . 11)]. Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors , Angiotensin Receptor Blockers , or Beta - Blockers
Clinical Impact :	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention :	During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions ( 5 . 6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact :	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention :	During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions ( 5 . 6)].
Lithium
Clinical Impact :	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology ( 12 . 3)].
Intervention :	During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact :	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention :	During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact :	Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention :	During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact :	Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions ( 5 . 2)].
Intervention :	The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact :	Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention :	During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion–the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide(including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide(including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄, and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5’-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.

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Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( 7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( 7)
Phenytoin	Monitor phenytoin level ( 7)
Methotrexate	Monitor for methotrexate toxicity ( 7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine ( 7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin ( 7)

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Inhibitors of CYP2D6
Clinical Impact:	The concomitant use of tramadol hydrochloride extended-release tablets and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride extended-release tablets is achieved. Since M1 is a more potent µ-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease and the M1 plasma concentration will increase which could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, and may cause potentially fatal respiratory depression [see Clinical Pharmacology (12.3)].
Intervention:	If concomitant use of a CYP2D6 inhibitor is necessary, follow patients closely for adverse reactions including opioid withdrawal, seizures, and serotonin syndrome. If a CYP2D6 inhibitor is discontinued, consider lowering tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved. Follow patients closely for adverse events including respiratory depression and sedation.
Examples	Quinidine, fluoxetine, paroxetine and bupropion
Inhibitors of CYP3A4
Clinical Impact:	The concomitant use of tramadol hydrochloride extended-release tablets and CYP3A4 inhibitors can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1. Follow patients closely for increased risk of serious adverse events including seizures and serotonin syndrome, and adverse reactions related to opioid toxicity including potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride extended-release tablets is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy and possibly signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol.
Intervention:	If concomitant use is necessary, consider dosage reduction of tramadol hydrochloride extended-release tablets until stable drug effects are achieved. Follow patients closely for seizures and serotonin syndrome, and signs of respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved and follow patients for signs and symptoms of opioid withdrawal.
Examples	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact:	The concomitant use of tramadol hydrochloride extended-release tablets and CYP3A4 inducers can decrease the plasma concentration of tramadol [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol, [see Warnings and Precautions (5.5)]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause seizures and serotonin syndrome, and potentially fatal respiratory depression.
Intervention:	If concomitant use is necessary, consider increasing the tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved. Follow patients for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider tramadol hydrochloride extended-release tablets dosage reduction and monitor for seizures and serotonin syndrome, and signs of sedation and respiratory depression. Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of tramadol hydrochloride extended-release tablets and carbamazepine is not recommended.
Examples:	Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.6)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue tramadol hydrochloride extended-release tablets if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.7)] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
Intervention:	Do not use tramadol hydrochloride extended-release tablets in patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of tramadol hydrochloride extended-release tablets and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Tramadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of tramadol hydrochloride extended-release tablets and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when tramadol hydrochloride extended-release tablets are used concomitantly with anticholinergic drugs.
Digoxin
Clinical Impact:	Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity.
Intervention:	Follow patients for signs of digoxin toxicity and adjust the dosage of digoxin as needed.
Warfarin
Clinical Impact:	Post-marketing surveillance of tramadol has revealed rare reports of alteration of warfarin effect, including elevation of prothrombin times.
Intervention:	Monitor the prothrombin time of patients on warfarin for signs of an interaction and adjust the dosage of warfarin as needed.

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Increased Risk of Myopathy/Rhabdomyolysis (2, 5.1, 7, 12.3)
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
Lopinavir plus ritonavir	Use lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9-Hydroxy- Risperidone (RatioChange relative to reference)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	C_max
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Factors	Dosage Adjustments for Aripiprazole
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
Known CYP2D6 Poor Metabolizersand strong CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors	Administer half of usual dose
Strong CYP2D6 and CYP3A4inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double usual dose over 1 to 2 weeks

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Table 5 Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours in healthy adult subjects (n=24)
Concomitant Drug	C_maxSS (Peak plasma concentration)	AUC_ss(0–12h) (Extent of systemic exposure)
Erythromycin (500 mg every 8 hrs)	+82%	+109%

Ketoconazole (400 mg once daily)	+135%	+164%

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Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin Tablets, USP
Drug(s)	Recommendation		Comments
Tizanidine	Contraindicated		Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [ see Contraindications ( 4.2 )]
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)		Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate. [See Warnings and Precautions ( 5.6 ).]
Drugs Known to Prolong QT Interval	Avoid Use		Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions ( 5.10 ) and Use in Specific Populations ( 8.5 )].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated		Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [See Adverse Reactions ( 6.1).]
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)		To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)		Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)		The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels		Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution		Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions ( 5.15)].
Clozapine	Use with caution		Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs	Use with caution		Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution Two-fold increase in exposure		Monitor for sildenafil toxicity (see Pharmacokinetics 12.3).
Duloxetine	Avoid Use Five-fold increase in duloxetine exposure		If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life		Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin Tablets, USP
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)		Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration. ( 2 )].		Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid		Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)		Potentiation of ciprofloxacin toxicity may occur.

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Drugs That May Potentiate Renal Dysfunction
Antibiotics	Antineoplastics	Anti-inflammatory Drugs	Gastrointestinal Agents
ciprofloxacin gentamicin tobramycin vancomycin trimethoprim with sulfamethoxazole	melphalan	azapropazon colchicine diclofenac naproxen sulindac	cimetidine ranitidine
	Antifungals		cimetidine ranitidine
	amphotericin B ketoconazole		Immunosuppressives
			tacrolimus
			Other Drugs
			fibric acid derivatives (e.g., bezafibrate, fenofibrate) methotrexate

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Antiretrovirals
Clinical Impact:	The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. • Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3)]. • Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)]. • There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
Intervention:	Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications (4)]. Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:	Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention:	Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact:	Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].
Intervention:	A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact:	Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)]. There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention:	Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6)].
Citalopram
Clinical Impact:	Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention:	Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:	Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].
Intervention:	Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:	Potential for increased exposure of phenytoin.
Intervention:	Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:	Increased exposure of diazepam [see Clinical Pharmacology (12.3)].
Intervention:	Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:	Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention:	Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:	Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:	Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)]. See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:	Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:	See Contraindications, Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact:	Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention:	Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:	Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10),Clinical Pharmacology (12.2)].
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:	Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact:	There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:	An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:	There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:	Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.

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Table 2: Drug-Thyroidal Axis Interactions
	Drug or Drug Class		Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
		Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
		Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
		Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
		Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
		Amiodarone Iodide (including iodine- containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
	Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
	Drugs that may increase		Drugs that may decrease
	serum TBG concentration		serum TBG concentration
	Clofibrate		Androgens / Anabolic Steroids
	Estrogen-containing oral		Asparaginase
	contraceptives		Glucocorticoids
	Estrogens (oral)		Slow-Release Nicotinic Acid
	Heroin / Methadone
	5-Fluorouracil
	Mitotane
	Tamoxifen
	Drugs that may cause protein-binding site displacement
	Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)		Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
	Carbamazepine Hydantoins Phenobarbital Rifampin		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
	Drugs that may decrease T ₄ 5' - deiodinase activity
	Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)		Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, Ieading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
	Miscellaneous
	Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives		Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
	Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
	Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin		Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
	Cardiac Glycosides		Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
	Cytokines - Interferon-α - Interleukin-2		Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
	Growth Hormones - Somatrem - Somatropin		Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
	Ketamine		Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
	Methylxanthine Bronchodilators - (e.g., Theophylline)		Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
	Radiographic Agents		Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
	Sympathomimetics		Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
	Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics		These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Drug	Description of Interaction
Tolbutamide; Sulfonylureas	Hypoglycemia potentiated
Methotrexate	Decreases tubular reabsorption; clinical toxicity from methotrexate can result
Oral Anticoagulant	Increased bleeding

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Table 3Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

Table name:

edema
hereditary coumarin resistance
hyperlipemia

hypothyroidism
nephrotic syndrome

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AED Co - administered	AED Concentration	Topiramate Concentration
Phenytoin	NCor25%increase ^a	48%decrease
Carbamazepine(CBZ)	NC	40%decrease
CBZepoxide ^b	NC	NE
Valproic acid	11%decrease	14%decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NCatTPM dosesupto400 mg/day	13%decrease

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Table 4: Clinically Relevant Interactions Affecting Omeprazole When Co-Administered with Other Drugs
CYP2C19 or CYP3A4 Inducers
Clinical Impact:	Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention:	St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions (5.9)]. Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:	Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
Intervention:	Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole.

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( 7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( 7)
Phenytoin	Monitor phenytoin level ( 7)
Methotrexate	Monitor for methotrexate toxicity ( 7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine ( 7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin ( 7)

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Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine,danazol	Do not exceed 10 mg simvastatindaily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem	Do not exceed 40 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine concentrations approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine and carbamazepine epoxide	? carbamazepine epoxide	May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Table 5. Established Drug Interactions Based on Drug Interaction Trials
Concomitant Drug Class: Drug Name	Effect on Concentration	Clinical Comments
ANGIOTENSIN RECEPTOR BLOCKERS e.g.
valsartan^* losartan^* candesartan^*	↑ angiotensin receptor blockers	Decrease the dose of the angiotensin receptor blockers and monitor patients for signs and symptoms of hypotension and/or worsening renal function. If such events occur, consider further dose reduction of the angiotensin receptor blocker or switching to an alternative to the angiotensin receptor blocker.
ANTIARRHYTHMICS
amiodarone^, bepridil^, disopyramide^, flecainide^, lidocaine (systemic)^, mexiletine^, propafenone^, quinidine^	↑ antiarrhythmics	For contraindicated antiarrhythmics [see Contraindications (4)]. Therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with VIEKIRA PAK.
ANTIDIABETIC DRUGS
metformin	↔ metformin	Monitor for signs of onset of lactic acidosis such as respiratory distress, somnolence, and non-specific abdominal distress or worsening renal function. Concomitant metformin use in patients with renal insufficiency or hepatic impairment is not recommended. Refer to the prescribing information of metformin for further guidance.
ANTIFUNGALS
ketoconazole	↑ ketoconazole	When VIEKIRA PAK is co-administered with ketoconazole, the maximum daily dose of ketoconazole should be limited to 200 mg per day.
voriconazole^*	↓ voriconazole	Co-administration of VIEKIRA PAK with voriconazole is not recommended unless an assessment of the benefit-to-risk ratio justifies the use of voriconazole.
ANTIPSYCHOTICS
quetiapine^*	↑ quetiapine	For contraindicated antipsychotics [see Contraindications (4)]. Initiation of VIEKIRA PAK in patients taking quetiapine: Consider alternative anti-HCV therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6^th of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for the recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking VIEKIRA PAK: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
CALCIUM CHANNEL BLOCKERS
amlodipine nifedipine^* diltiazem^* verapamil^*	↑ calcium channel blockers	Decrease the dose of the calcium channel blocker. The dose of amlodipine should be decreased by at least 50%. Clinical monitoring of patients is recommended for edema and/or signs and symptoms of hypotension. If such events occur, consider further dose reduction of the calcium channel blocker or switching to an alternative to the calcium channel blocker.
CORTICOSTEROIDS (INHALED/NASAL)
fluticasone^*	↑ fluticasone	Concomitant use of VIEKIRA PAK with inhaled or nasal fluticasone may reduce serum cortisol concentrations. Alternative corticosteroids should be considered, particularly for long term use.
DIURETICS
furosemide	↑ furosemide (C_max)	Clinical monitoring of patients is recommended and therapy should be individualized based on patient’s response.
HIV-ANTIVIRAL AGENTS
atazanavir/ritonavir once daily	↑ paritaprevir	When coadministered with VIEKIRA PAK, atazanavir 300 mg (without ritonavir) should only be given in the morning.
darunavir/ritonavir	↓ darunavir (C_trough)	Treatment naïve patients or treatment experienced patients with no darunavir associated substitutions: Darunavir 800 mg once daily (without ritonavir) can be co-administered with VIEKIRA PAK. Treatment experienced patients with at least one darunavir resistance associated substitution or with no baseline resistance information: Co-administration of darunavir/ritonavir 600/100 mg twice daily with VIEKIRA PAK is not recommended.
lopinavir/ritonavir	↑ paritaprevir	Co-administration of VIEKIRA PAK with lopinavir/ritonavir is not recommended.
rilpivirine	↑ rilpivirine	For contraindicated non-nucleoside reverse transcriptase inhibitors [see Contraindications (4)]. Co-administration of VIEKIRA PAK with rilpivirine once daily is not recommended due to potential for QT interval prolongation with higher concentrations of rilpivirine.
HMG CoA REDUCTASE INHIBITORS
rosuvastatin	↑ rosuvastatin	For contraindicated HMG-CoA Reductase Inhibitors [see Contraindications (4)]. When VIEKIRA PAK is co-administered with rosuvastatin, the dose of rosuvastatin should not exceed 10 mg per day.
pravastatin	↑ pravastatin	When VIEKIRA PAK is co-administered with pravastatin, the dose of pravastatin should not exceed 40 mg per day.
IMMUNOSUPPRESSANTS
cyclosporine	↑ cyclosporine	For contraindicated immunosuppressants [see Contraindications (4)]. When initiating therapy with VIEKIRA PAK, reduce cyclosporine dose to 1/5^th of the patient’s current cyclosporine dose. Measure cyclosporine blood concentrations to determine subsequent dose modifications. Upon completion of VIEKIRA PAK therapy, the appropriate time to resume pre-VIEKIRA PAK dose of cyclosporine should be guided by assessment of cyclosporine blood concentrations. Frequent assessment of renal function and cyclosporine-related side effects is recommended.
LONG ACTING BETA-ADRENOCEPTOR AGONIST
salmeterol^*	↑ salmeterol	Concurrent administration of VIEKIRA PAK and salmeterol is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
MUSCLE RELAXANTS
carisoprodol	↓ carisoprodol ↔ mepobramate (metabolite of carisoprodol)	Increase dose if clinically indicated.
cyclobenzaprine	↓cyclobenzaprine ↓norcyclobenzaprine (metabolite of cyclobenzaprine)	Increase dose if clinically indicated.
NARCOTIC ANALGESICS
buprenorphine/ naloxone	↑ buprenorphine ↑ norbuprenorphine (metabolite of buprenorphine)	Patients should be closely monitored for sedation and cognitive effects.
Acetaminophen/ hydrocodone	↑ hydrocodone ↔ acetaminophen	Reduce the dose of hydrocodone by 50% and monitor patients for respiratory depression and sedation at frequent intervals. Upon completion of VIEKIRA PAK therapy, adjust the hydrocodone dose and monitor for signs of opioid withdrawal.
PROTON PUMP INHIBITORS
omeprazole	↓ omeprazole	Monitor patients for decreased efficacy of omeprazole. Consider increasing the omeprazole dose in patients whose symptoms are not well controlled; avoid use of more than 40 mg per day of omeprazole.
SEDATIVES/HYPNOTICS
alprazolam	↑ alprazolam	For contraindicated Sedatives/Hypnotics [see Contraindications (4)]. Clinical monitoring of patients is recommended. A decrease in alprazolam dose can be considered based on clinical response.
diazepam	↓ diazepam ↓ nordiazepam (metabolite of diazepam)	Increase dose if clinically indicated.
See Clinical Pharmacology, Tables 8 and 9 . The direction of the arrow indicates the direction of the change in exposures (C_max and AUC) (↑ = increase of more than 20%, ↓ = decrease of more than 20%, ↔ = no change or change less than 20%). ^*not studied.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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AED Co - administered	AED Concentration	Topiramate Concentration
Phenytoin	NCor25%increase^a	48%decrease
Carbamazepine(CBZ)	NC	40%decrease
CBZepoxide^b	NC	NE
Valproic acid	11%decrease	14%decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NCatTPM dosesupto400 mg/day	13%decrease

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Interacting DrugInteracting Drug	InteractionInteraction
Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products ( 2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents	Carefully monitor blood glucose ( 5.12, 7.3)

Table name: AED CoadministeredAED ConcentrationTopiramate Concentration





Phenytoin	NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxideIs not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Table 7 Summary of AED Interactions with Oxcarbazepine
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400-2000	900	ncnc denotes a mean change of less than 10%	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100-150	600-1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250-500	600-1800 >1200-2400	nc ^, Pediatrics up to 40% increaseMean increase in adults at high oxcarbazepine doses [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400-2800	600-1800	nc	18% decrease [CI: 13% decrease, 40% decrease]

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Table 3Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Drugs That May Increase the Risk of Hypoglycemia
Drugs:	Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics
Intervention:	Dose reductions and increased frequency of glucose monitoring may be required when XULTOPHY 100/3.6 is co-administered with these drugs.
Drugs That May Decrease the Blood Glucose Lowering Effect of XULTOPHY 100/3.6
Drugs:	Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones.
Intervention:	Dose increases and increased frequency of glucose monitoring may be required when XULTOPHY 100/3.6 is co-administered with these drugs.
Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of XULTOPHY 100/3.6
Drugs:	Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.
Intervention:	Dose adjustment and increased frequency of glucose monitoring may be required when XULTOPHY 100/3.6 is co-administered with these drugs.
Drugs That May Blunt Signs and Symptoms of Hypoglycemia
Drugs:	Beta-blockers, clonidine, guanethidine, and reserpine
Intervention:	Increased frequency of glucose monitoring may be required when XULTOPHY 100/3.6 is co-administered with these drugs.

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Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
* The interaction between VIRAMUNE and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.
Drug Name	Effect on Concentration of Nevirapine or Concomitant Drug	Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir*	↓ Atazanavir ↑ Nevirapine	Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir*	↓ Amprenavir ↑ Nevirapine	Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir*	↓ Amprenavir ↑ Nevirapine	No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir*	↓ Indinavir	The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir*	↓Lopinavir	Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra^® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir*	↓Nelfinavir M8 Metabolite ↓Nelfinavir C_min	The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/ritonavir	The interaction between nevirapine and saquinavir/ritonavir has not been evaluated	The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz*	↓ Efavirenz	The appropriate doses of these combinations with respect to safety and efficacy have not been established.
Delavirdine Etravirine Rilpivirine		Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.
Hepatitis C Antiviral Agents
Boceprevir	Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine.	Nevirapine and boceprevir should not be coadministered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy.
Telaprevir	Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir.	Nevirapine and telaprevir should not be coadministered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events.
Other Agents
Analgesics:
Methadone*	↓ Methadone	Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics:
Amiodarone, disopyramide, lidocaine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Antibiotics:
Clarithromycin*	↓ Clarithromycin ↑ 14-OH clarithromycin	Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Rifabutin*	↑ Rifabutin	Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin*	↓ Nevirapine	Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants: Carbamazepine, clonazepam, ethosuximide	Plasma concentrations of nevirapine and the anticonvulsant may be decreased.	Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals:
Fluconazole*	↑Nevirapine	Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Ketoconazole*	↓ Ketoconazole	Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Itraconazole	↓ Itraconazole	Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics: Warfarin	Plasma concentrations may be increased.	Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers: Diltiazem, nifedipine, verapamil	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Cancer chemotherapy: Cyclophosphamide	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Ergot alkaloids: Ergotamine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Motility agents: Cisapride	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Opiate agonists: Fentanyl	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Oral contraceptives:
Ethinyl estradiol and Norethindrone*	↓ Ethinyl estradiol ↓ Norethindrone	Despite lower ethinyl estradiol and norethindrone exposures when coadministered with nevirapine, literature reports suggest that nevirapine has no effect on pregnancy rates among HIV-infected women on combined oral contraceptives. When coadministered with VIRAMUNE, no dose adjustment of ethinyl estradiol or norethindrone is needed when used in combination for contraception. When these oral contraceptives are used for hormonal regulation during VIRAMUNE therapy, the therapeutic effect of the hormonal therapy should be monitored.

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Table 3 Established and Other Potentially Significant This table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
Concomitant Drug Class: Drug Name	Effect	Clinical Comment
HIV antiviral agents
Protease inhibitor: atazanavir	↓atazanavir ↑ tenofovir	Coadministration of atazanavir with ATRIPLA is not recommended. Coadministration of atazanavir with either efavirenz or tenofovir DF decreases plasma concentrations of atazanavir. The combined effect of efavirenz plus tenofovir DF on atazanavir plasma concentrations is not known. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA.
Protease inhibitor: fosamprenavir calcium	↓ amprenavir	Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and ATRIPLA with respect to safety and efficacy have not been established. Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when ATRIPLA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when ATRIPLA is administered with fosamprenavir plus ritonavir twice daily.
Protease inhibitor: indinavir	↓ indinavir	The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz.
Protease inhibitor: lopinavir/ritonavir	↓ lopinavir ↑ tenofovir	Do not use once daily administration of lopinavir/ritonavir. Dose increase of lopinavir/ritonavir is recommended for all patients when coadministered with efavirenz. Refer to the full prescribing information for lopinavir/ritonavir for guidance on coadministration with efavirenz- or tenofovir-containing regimens, such as ATRIPLA. Patients should be monitored for tenofovir-associated adverse reactions.
Protease inhibitor: ritonavir	↑ ritonavir ↑ efavirenz	When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when ATRIPLA is used in combination with ritonavir.
Protease inhibitor: saquinavir	↓ saquinavir	Appropriate doses of the combination of efavirenz and saquinavir/ritonavir with respect to safety and efficacy have not been established.
CCR5 co-receptor antagonist: maraviroc	↓ maraviroc	Efavirenz decreases plasma concentrations of maraviroc. Refer to the full prescribing information for maraviroc for guidance on coadministration with ATRIPLA.
NRTI: didanosine	↑ didanosine	Coadministration of ATRIPLA and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions including pancreatitis, lactic acidosis, and neuropathy. A dose reduction of didanosine is recommended when coadministered with tenofovir DF. For additional information on coadministration with tenofovir DF-containing products, please refer to the didanosine prescribing information.
NNRTI: Other NNRTIs	↑ or ↓ efavirenz and/or NNRTI	Combining two NNRTIs has not been shown to be beneficial. ATRIPLA contains efavirenz and should not be coadministered with other NNRTIs.
Integrase strand transfer inhibitor: raltegravir	↓ raltegravir	Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
Hepatitis C antiviral agents
Protease inhibitor: boceprevir	↓ boceprevir	Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with efavirenz, which may result in loss of therapeutic effect. The combination should be avoided.
Protease inhibitor: simeprevir	↓ simeprevir ↔ efavirenz	Concomitant administration of simeprevir with efavirenz is not recommended because it may result in loss of therapeutic effect of simeprevir.
NS5A inhibitor/NS5B polymerase inhibitor : ledipasvir/sofosbuvir	↑ tenofovir	Patients receiving ATRIPLA and HARVONI ^® (ledipasvir/sofosbuvir) concomitantly should be monitored for adverse reactions associated with tenofovir DF.
Other agents
Anticoagulant: warfarin	↑ or ↓ warfarin	Plasma concentrations and effects potentially increased or decreased by efavirenz.
Anticonvulsants: carbamazepine	↓ carbamazepine ↓ efavirenz	There are insufficient data to make a dose recommendation for ATRIPLA. Alternative anticonvulsant treatment should be used.
phenytoin phenobarbital	↓ anticonvulsant ↓ efavirenz	Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
Antidepressants: bupropion	↓ buproprion	The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded.
sertraline	↓ sertraline	Increases in sertraline dose should be guided by clinical response.
Antifungals: itraconazole	↓ itraconazole ↓ hydroxy-itraconazole	Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
ketoconazole	↓ ketoconazole	Drug interaction trials with ATRIPLA and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole.
posaconazole	↓ posaconazole	Avoid concomitant use unless the benefit outweighs the risks.
Anti-infective: clarithromycin	↓ clarithromycin ↑ 14-OH metabolite	Clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of ATRIPLA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with ATRIPLA.
Antimycobacterial: rifabutin	↓ rifabutin	Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
rifampin	↓ efavirenz	If ATRIPLA is coadministered with rifampin to patients weighing 50 kg or more, an additional 200 mg/day of efavirenz is recommended.
Antimalarials: artemether/lumefantrine	↓ artemether ↓ dihydroartemisinin ↓ lumefantrine	Artemether/lumefantrine should be used cautiously with ATRIPLA because decreased artemether, dihydroartemisinin (active metabolite of artemether), and/or lumefantrine concentrations may result in a decrease of antimalarial efficacy of artemether/lumefantrine.
Calcium channel blockers: diltiazem	↓ diltiazem ↓ desacetyl diltiazem ↓ N-monodes-methyl diltiazem	Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of ATRIPLA is necessary when administered with diltiazem.
Others (e.g., felodipine, nicardipine, nifedipine, verapamil)	↓ calcium channel blocker	No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker).
HMG-CoA reductase inhibitors: atorvastatin pravastatin simvastatin	↓ atorvastatin ↓ pravastatin ↓ simvastatin	Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with efavirenz. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
Hormonal contraceptives:
Oral: ethinyl estradiol/norgestimate	↓ active metabolites of norgestimate	A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed.
Implant: etonogestrel	↓ etonogestrel	A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.
Immunosuppressants: cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A	↓ immuno-suppressant	Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by efavirenz. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with ATRIPLA.
Narcotic analgesic: methadone	↓ methadone	Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.

Table name:

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine, danazol	Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem	Do not exceed 40 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

Table name:

Table 25: Clinically Important Drug Interactions with Aripiprazole:
Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)] .	With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)] .
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)] .	With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)] .
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.8)] .
Benzodiazepines (e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.8)] .	Monitor sedation and blood pressure. Adjust dose accordingly.

Table name:

Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitors (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

Table name:

Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*

* Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol, systemic and inhaled	amoxicillin
ampicillin, with or without sulbactam	atenolol
azithromycin	caffeine, dietary ingestion
cefaclor	co-trimoxizole (trimethoprim and sulfamethoxazole)
diltiazem	dirithromycin
enflurane	famotidine
felodipine	finasteride
hydrocortisone	isoflurane
isoniazid	isradipine
influenza vaccine	ketoconazole
lomefloxacin	mebendazole
medroxyprogesterone	methylprednisolone
metronidazole	metoprolol
nadolol	nifedipine
nizatidine	norfloxacin
ofloxacin	omeprazole
prednisone, prednisolone	ranitidine
rifabutin	roxithromycin
sorbitol (purgative doses do not inhibit theophylline absorption)	sucralfate
terfenadine	terbutaline, systemic
tocainide	tetracycline

Table name:

Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)	VIAGRA 25 mg
Supine	7.4 (-0.9, 15.7)
Standing	6.0 (-0.8, 12.8)

Table name: Decreased Moxifloxacin Hydrochloride absorption. Take Moxifloxacin Hydrochloride Tablet at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3)Anticoagulant effect enhanced. Monitor prothrombin time/INR, and bleeding. (6, 7.2, 12.3)Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.3, 7.4)Carefully monitor blood glucose. (5.10, 7.3)


Interacting Drug	Interaction
Multivalent cation-containing products including : antacids, sucralfate, multivitamins
Warfarin
Class IA and Class III antiarrhythmics:
Antidiabetic agents

Table name:

Table 8: Clinically Significant Drug Interactions with Clarithromycin
Drugs That Are Affected By Clarithromycin
Drug(s) with Pharmacokinetics Affected by Clarithromycin	Recommendation	Comments
Antiarrhythmics:
Disopyramide Quinidine Dofetilide Amiodarone Sotalol Procainamide	Not Recommended	Disopyramide, Quinidine: There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs [see Warnings and Precautions (5.3)] . Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine. There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.
Digoxin	Use With Caution	Digoxin: Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are co-administered, inhibition of Pgp by clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range.
Oral Anticoagulants:
Warfarin	Use With Caution	Oral anticoagulants: Spontaneous reports in the postmarketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously [see Warnings and Precautions (5.4)] .
Antiepileptics:
Carbamazepine	Use With Caution	Carbamazepine: Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered. Increased serum concentrations of carbamazepine were observed in clinical trials with clarithromycin. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with carbamazepine.
Antifungals:
Itraconazole	Use With Caution	Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly (see also Itraconazole under “Drugs That Affect Clarithromycin” in the table below). Clarithromycin may increase the plasma concentrations of itraconazole. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions.
Fluconazole	No Dose Adjustment	Fluconazole: [see Pharmacokinetics (12.3)]
Anti-Gout Agents:
Colchicine (in patients with renal or hepatic impairment)	Contraindicated	Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. The dose of colchicine should be reduced when co-administered with clarithromycin in patients with normal renal and hepatic function [see Contraindications (4.4) and Warnings and Precautions (5.4)] .
Colchicine (in patients with normal renal and hepatic function)	Use With Caution
Antipsychotics:
Pimozide	Contraindicated	Pimozide: [See Contraindications (4.2)]
Quetiapine		Quetiapine: Quetiapine is a substrate for CYP3A4, which is inhibited by clarithromycin. Co-administration with clarithromycin could result in increased quetiapine exposure and possible quetiapine related toxicities. There have been postmarketing reports of somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation during concomitant administration. Refer to quetiapine prescribing information for recommendations on dose reduction if co-administered with CYP3A4 inhibitors such as clarithromycin.
Antispasmodics:
Tolterodine (patients deficient in CYP2D6 activity)	Use With Caution	Tolterodine: The primary route of metabolism for tolterodine is via CYP2D6. However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when co-administered with clarithromycin.
Antivirals:
Atazanavir	Use With Caution	Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)] .
Saquinavir (in patients with decreased renal function)		Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction (see Saquinavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)] .
Ritonavir Etravirine		Ritonavir, Etravirine: (see Ritonavir and Etravirine under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)] .
Maraviroc		Maraviroc: Clarithromycin may result in increases in maraviroc exposures by inhibition of CYP3A metabolism. See Selzentry ^® prescribing information for dose recommendation when given with strong CYP3A inhibitors such as clarithromycin.
Boceprevir (in patients with normal renal function) Didanosine	No Dose Adjustment	Boceprevir: Both clarithromycin and boceprevir are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when co-administered. No dose adjustments are necessary for patients with normal renal function (see Victrelis ^® prescribing information).
Zidovudine		Zidovudine: Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Administration of clarithromycin and zidovudine should be separated by at least two hours [see Pharmacokinetics (12.3)] . The impact of co-administration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated.
Calcium Channel Blockers:
Verapamil	Use With Caution	Verapamil: Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, [see Warnings and Precautions (5.4)] .
Amlodipine Diltiazem		Amlodipine, Diltiazem: [See Warnings and Precautions (5.4)]
Nifedipine		Nifedipine: Nifedipine is a substrate for CYP3A. Clarithromycin and other macrolides are known to inhibit CYP3A. There is potential of CYP3A-mediated interaction between nifedipine and clarithromycin. Hypotension and peripheral edema were observed when clarithromycin was taken concomitantly with nifedipine [see Warnings and Precautions (5.4)] .
Ergot Alkaloids:
Ergotamine Dihydroergotamine	Contraindicated	Ergotamine, Dihydroergotamine: Postmarketing reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4.6)] .
Gastroprokinetic Agents:
Cisapride	Contraindicated	Cisapride: [See Contraindications (4.2)]
HMG-CoA Reductase Inhibitors:
Lovastatin Simvastatin	Contraindicated	Lovastatin, Simvastatin, Atorvastatin, Pravastatin, Fluvastatin: [See Contraindications (4.5) and Warnings and Precautions (5.4)]
Atorvastatin Pravastatin	Use With Caution
Fluvastatin	No Dose Adjustment
Hypoglycemic Agents:
Nateglinide Pioglitazone Repaglinide Rosiglitazone	Use With Caution	Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]
Insulin		Insulin: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]
Immunosuppressants:
Cyclosporine	Use With Caution	Cyclosporine: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine.
Tacrolimus		Tacrolimus: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with tacrolimus.
Phosphodiesterase inhibitors:
Sildenafil Tadalafil Vardenafil	Use With Caution	Sildenafil, Tadalafil, Vardenafil: Each of these phosphodiesterase inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant administration of clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil, or vardenafil will result in increased exposure of these phosphodiesterase inhibitors. Co-administration of these phosphodiesterase inhibitors with clarithromycin is not recommended. Increased systemic exposure of these drugs may occur with clarithromycin; reduction of dosage for phosphodiesterase inhibitors should be considered (see their respective prescribing information).
Proton Pump Inhibitors:
Omeprazole	No Dose Adjustment	Omeprazole: The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when coadministered with clarithromycin as a result of increased omeprazole exposures [see Pharmacokinetics (12.3)] (see also Omeprazole under “Drugs That Affect Clarithromycin” in the table below).
Xanthine Derivatives:
Theophylline	Use With Caution	Theophylline: Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations [see Pharmacokinetics (12.3)] . Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range.
Triazolobenzodiazepines and Other Related Benzodiazepines:
Midazolam	Use With Caution	Midazolam: When oral midazolam is co-administered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated [see Warnings and Precautions (5.4) and Pharmacokinetics (12.3)] .
Alprazolam Triazolam		Triazolam, Alprazolam: Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is co-administered with clarithromycin. There have been postmarketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested. In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines.
Temazepam Nitrazepam Lorazepam	No Dose Adjustment	Temazepam, Nitrazepam, Lorazepam: For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.
Cytochrome P450 Inducers:
Rifabutin	Use With Caution	Rifabutin: Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis (see Rifabutin under “Drugs That Affect Clarithromycin” in the table below).
Other Drugs Metabolized by CYP3A:
Alfentanil Bromocriptine Cilostazol Methylprednisole Vinblastine Phenobarbital St. John’s Wort	Use With Caution	There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort.
Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A:
Hexobarbital Phenytoin Valproate	Use With Caution	There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.
Drugs that Affect Clarithromycin
Drug(s) that Affect the Pharmacokinetics of Clarithromycin	Recommendation	Comments
Antifungals:
Itraconazole	Use With Caution	Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions (see also Itraconazole under “Drugs That Are Affected By Clarithromycin” in the table above).
Antivirals:
Atazanavir	Use With Caution	Atazanavir: When clarithromycin is co-administered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology (12.3)] . Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.
Ritonavir (in patients with decreased renal function)		Ritonavir: Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with ritonavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium [see Pharmacokinetics (12.3)] . Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.
Saquinavir (in patients with decreased renal function)		Saquinavir: When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (refer to ritonavir above) [see Pharmacokinetics (12.3)] .
Etravirine		Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.
Saquinavir (in patients with normal renal function)	No Dose Adjustment
Ritonavir (in patients with normal renal function)
Proton Pump Inhibitors:
Omeprazole	Use With Caution	Omeprazole: Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole [see Pharmacokinetics (12.3)] .
Miscellaneous Cytochrome P450 Inducers:
Efavirenz Nevirapine Rifampicin Rifabutin Rifapentine	Use With Caution	Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are Affected By Clarithromycin” in the table above).

Table name: Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol) In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. During concomitant use of diclofenac sodium topical gel and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of diclofenac sodium topical gel and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.

•
Drugs That Interfere with Hemostasis
Clinical Impact:
Intervention:	Monitor patients with concomitant use of diclofenac sodium topical gel with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention:	Concomitant use of diclofenac sodium topical gel and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Diclofenac sodium topical gel is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:
Intervention:
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of diclofenac sodium topical gel with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact:	The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of diclofenac sodium topical gel and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of diclofenac sodium topical gel and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of diclofenac sodium topical gel and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of diclofenac sodium topical gel and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention:	During concomitant use of diclofenac sodium topical gel and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention:	The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of diclofenac sodium topical gel and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of diclofenac sodium topical gel and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and Gl toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.

Table name:

Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)	VIAGRA 25 mg
Supine	7.4 (-0.9, 15.7)
Standing	6.0 (-0.8, 12.8)

Table name:

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C Protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

Table name:

Digoxin concentrations increased greater than 50%
	Digoxin Serum Concentration Increase	Digoxin AUC Increase	Recommendations
NA – Not available/reported
Amiodarone	70%	NA	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30 to 50% or by modifying the dosing frequency and continue monitoring.
Captopril	58%	39%
Clarithromycin	NA	70%
Dronedarone	NA	150%
Gentamicin	129 to 212%	NA
Erythromycin	100%	NA
Itraconazole	80%	NA
Lapatinib	NA	180%
Nitrendipine	57%	15%
Propafenone	NA	60 to 270%
Quinidine	100%	NA
Ranolazine	50%	NA
Ritonavir	NA	86%
Telaprevir	50%	85%
Tetracycline	100%	NA
Verapamil	50 to 75%	NA
Digoxin concentrations increased less than 50%
Atorvastatin	22%	15%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15 to 30% or by modifying the dosing frequency and continue monitoring.
Carvedilol	16%	14%
Conivaptan	33%	43%
Diltiazem	20%	NA
Indomethacin	40%	NA
Nefazodone	27%	15%
Nifedipine	45%	NA
Propantheline	24%	24%
Quinine	NA	33%
Raberprazole	29%	19%
Saquinavir	27%	49%
Spironolactone	25%	NA
Telmisartan	20 to 49%	NA
Tricagrelor	31%	28%
Tolvaptan	30%	NA
Trimethoprim	22 to 28%	NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John's Wort, sucralfate, sulfasalazine			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20 to 40% as necessary.

Table name:

DRUGS	EFFECT
Aspirin w/anti-inflammatory agents	Increased ulcerogenic effects.
Butalbital w/coumarin anticoagulants	Decreased effect of anticoagulant because of increased metabolism resulting from enzyme induction.
Butalbital w/tricyclic antidepressants	Decreased blood levels of the antidepressant.

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.12, 7.3)

Table name:

CONCOMITANT DRUG	CLINICAL EFFECT(S)
Amphetamines, cocaine, other sympathomimetic agents	Additive hypertension, tachycardia, possibly cardiotoxicity
Atropine, scopolamine, antihistamines, other anticholinergic agents	Additive or super-additive tachycardia, drowsiness
Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants	Additive tachycardia, hypertension, drowsiness
Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants	Additive drowsiness and CNS depression
Disulfiram	A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge
Fluoxetine	A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days
Antipyrine, barbiturates	Decreased clearance of these agents, presumably via competitive inhibition of metabolism
Theophylline	Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco
Opioids	Cross-tolerance and mutual potentiation
Naltrexone	Oral THC effects were enhanced by opioid receptor blockade.
Alcohol	Increase in the positive subjective mood effects of smoked marijuana

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Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate[see Warnings and Precautions (5.6).]
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [see Adverse Reactions (6.1).]
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution 2-fold increase in exposure	Monitor for sildenafil toxicity (see Pharmacokinetics -(12.3)-].
Duloxetine	Avoid Use 5-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx^® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2)].	Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

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Table 5 Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug Name	Effect on Concentration of Boceprevir or Concomitant Drug	Recommendations
Antiarrhythmics: amiodarone, bepridil, propafenone, quinidine	↑ antiarrhythmics	Coadministration with VICTRELIS has the potential to produce serious and/or life-threatening adverse events and has not been studied. Caution is warranted and therapeutic concentration monitoring of these drugs is recommended if they are used concomitantly with VICTRELIS.
digoxin	↑ digoxin	Digoxin concentrations increased when administered with VICTRELIS [see Clinical Pharmacology (12.3)]. Measure serum digoxin concentrations before initiating VICTRELIS. Continue monitoring digoxin concentrations; consult the digoxin prescribing information for information on titrating the digoxin dose.
Anticoagulant: warfarin	↑ or ↓ warfarin	Concentrations of warfarin may be altered when co-administered with VICTRELIS. Monitor INR closely.
Antidepressants: trazodone, desipramine	↑ trazodone ↑ desipramine	Plasma concentrations of trazodone and desipramine may increase when administered with VICTRELIS, resulting in adverse events such as dizziness, hypotension and syncope. Use with caution and consider a lower dose of trazodone or desipramine.
escitalopram	↓escitalopram	Exposure of escitalopram was slightly decreased when coadministered with VICTRELIS. Selective serotonin reuptake inhibitors such as escitalopram have a wide therapeutic index, but doses may need to be adjusted when combined with VICTRELIS.
Antifungals: ketoconazoleThese combinations have been studied; see Clinical Pharmacology (12.3) for magnitude of interaction., itraconazole, posaconazole, voriconazole	↑ boceprevir ↑ itraconazole ↑ ketoconazole ↑ posaconazole ↑ voriconazole	Plasma concentrations of ketoconazole, itraconazole, voriconazole or posaconazole may be increased with VICTRELIS. When coadministration is required, doses of ketoconazole and itraconazole should not exceed 200 mg/day.
Anti-gout: colchicine	↑ colchicine	Significant increases in colchicine levels are expected; fatal colchicine toxicity has been reported with other strong CYP3A4 inhibitors. Patients with renal or hepatic impairment should not be given colchicine with VICTRELIS. Treatment of gout flares (during treatment with VICTRELIS): 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares (during treatment with VICTRELIS): If the original regimen was 0.6 mg twice a day, reduce dose to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, reduce the dose to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF) (during treatment with VICTRELIS): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Anti-infective: clarithromycin	↑ clarithromycin	Concentrations of clarithromycin may be increased with VICTRELIS; however, no dosage adjustment is necessary for patients with normal renal function.
Antimycobacterial: rifabutin	↓ boceprevir ↑ rifabutin	Increases in rifabutin exposure are anticipated, while exposure of boceprevir may be decreased. Doses have not been established for the 2 drugs when used in combination. Concomitant use is not recommended.
Calcium Channel Blockers such as: amlodipine, diltiazem, felodipine, nifedipine, nicardipine, nisoldipine, verapamil	↑ calcium channel blockers	Plasma concentrations of calcium channel blockers may increase when administered with VICTRELIS. Caution is warranted and clinical monitoring is recommended.
Corticosteroid, systemic: dexamethasone	↓ boceprevir	Coadministration of VICTRELIS with CYP3A4/5 inducers may decrease plasma concentrations of boceprevir, which may result in loss of therapeutic effect. Therefore, this combination should be avoided if possible and used with caution if necessary.
prednisone	↑ prednisone	Concentrations of prednisone and its active metabolite, prednisolone, increased when administered with VICTRELIS [see Clinical Pharmacology (12.3)]. No dose adjustment of prednisone is necessary when co-administered with VICTRELIS. Patients receiving prednisone and VICTRELIS should be monitored appropriately.
Corticosteroid, inhaled: budesonide, fluticasone	↑ budesonide ↑ fluticasone	Concomitant use of inhaled budesonide or fluticasone with VICTRELIS may result in increased plasma concentrations of budesonide or fluticasone, resulting in significantly reduced serum cortisol concentrations. Avoid coadministration if possible, particularly for extended durations.
Endothelin Receptor Antagonist: bosentan	↑ bosentan	Concentrations of bosentan may be increased when coadministered with VICTRELIS. Use with caution and monitor closely.
HIV Integrase Inhibitor: raltegravir	↔ raltegravir	No dose adjustment required for VICTRELIS or raltegravir.
HIV Non-Nucleoside Reverse Transcriptase Inhibitors: efavirenz	↓ boceprevir	Plasma trough concentrations of boceprevir were decreased when VICTRELIS was coadministered with efavirenz, which may result in loss of therapeutic effect. Avoid combination.
etravirine	↓ etravirine	Concentrations of etravirine decreased when coadministered with VICTRELIS. The clinical significance of the reductions in etravirine pharmacokinetic parameters has not been directly assessed.
rilpivirine	↑ rilpivirine	Concomitant administration of rilpivirine with VICTRELIS increased the exposure to rilpivirine. No dose adjustment of VICTRELIS or rilpivirine is recommended.
HIV Protease Inhibitors: atazanavir/ritonavir	↓ atazanavir ↓ ritonavir	Concomitant administration of boceprevir and atazanavir/ritonavir resulted in reduced steady-state exposures to atazanavir and ritonavir. Coadministration of atazanavir/ritonavir and boceprevir is not recommended.
darunavir/ritonavir	↓ darunavir ↓ ritonavir ↓ boceprevir	Concomitant administration of boceprevir and darunavir/ritonavir resulted in reduced steady-state exposures to boceprevir, darunavir and ritonavir. Coadministration of darunavir/ritonavir and boceprevir is not recommended.
lopinavir/ritonavir	↓ lopinavir ↓ ritonavir ↓ boceprevir	Concomitant administration of boceprevir and lopinavir/ritonavir resulted in reduced steady-state exposures to boceprevir, lopinavir and ritonavir. Coadministration of lopinavir/ritonavir and boceprevir is not recommended.
ritonavir	↓ boceprevir	When boceprevir is administered with ritonavir alone, boceprevir concentrations are decreased.
HMG-CoA Reductase Inhibitors:		For contraindicated HMG-CoA reductase inhibitors, [see Contraindications (4)].
atorvastatin	↑ atorvastatin	Exposure to atorvastatin was increased when administered with VICTRELIS. Use the lowest effective dose of atorvastatin, but do not exceed a daily dose of 40 mg when coadministered with VICTRELIS.
pravastatin	↑ pravastatin	Concomitant administration of pravastatin with VICTRELIS increased exposure to pravastatin. Treatment with pravastatin can be initiated at the recommended dose when coadministered with VICTRELIS. Close clinical monitoring is warranted.
Immunosuppressants: cyclosporine	↑cyclosporine	Dose adjustments of cyclosporine should be anticipated when administered with VICTRELIS and should be guided by close monitoring of cyclosporine blood concentrations, and frequent assessments of renal function and cyclosporine-related side effects.
tacrolimus	↑tacrolimus	Concomitant administration of VICTRELIS with tacrolimus requires significant dose reduction and prolongation of the dosing interval for tacrolimus, with close monitoring of tacrolimus blood concentrations and frequent assessments of renal function and tacrolimus-related side effects.
sirolimus	↑sirolimus	Concomitant administration of VICTRELIS with sirolimus requires significant dose reduction and prolongation of the dosing interval for sirolimus, with close monitoring of sirolimus blood concentrations and frequent assessments of renal function and sirolimus-related side effects.
Inhaled beta-agonist: salmeterol	↑ salmeterol	Concurrent use of inhaled salmeterol and VICTRELIS is not recommended due to the risk of cardiovascular events associated with salmeterol.
Narcotic Analgesic/Opioid Dependence: methadone	↓ R-methadone	Plasma concentrations of R-methadone decreased when coadministered with VICTRELIS [see Clinical Pharmacology (12.3)]. The observed changes are not considered clinically relevant. No dose adjustment of methadone or VICTRELIS is recommended. Individual patients may require additional titration of their methadone dosage when VICTRELIS is started or stopped to ensure clinical effect of methadone.
buprenorphine/naloxone	↑ buprenorphine/naloxone	Plasma concentrations of buprenorphine and naloxone increased when coadministered with VICTRELIS [see Clinical Pharmacology (12.3)]. The observed changes are not considered clinically relevant. No dose adjustment of buprenorphine/naloxone or VICTRELIS is recommended.
Oral hormonal contraceptives:		For contraindicated oral contraceptives, [see Contraindications (4)].
drospirenone/ethinyl estradiol	↑ drospirenone ↓ ethinyl estradiol	Concentrations of drospirenone increased in the presence of boceprevir. Thus, the use of drospirenone-containing products is contraindicated during treatment with VICTRELIS due to potential for hyperkalemia [see Contraindications (4)].
norethindrone/ethinyl estradiol	↓ ethinyl estradiol ↔ norethindrone	Concentrations of ethinyl estradiol decreased in the presence of boceprevir. Norethindrone C_max decreased 17% in the presence of boceprevir [see Clinical Pharmacology (12.3)]. Coadministration of VICTRELIS with a combined oral contraceptive containing ethinyl estradiol and at least 1 mg of norethindrone is not likely to alter the effectiveness of this combined oral contraceptive [see Use in Specific Populations (8.1)]. Patients using estrogens as hormone replacement therapy should be clinically monitored for signs of estrogen deficiency.
PDE5 inhibitors:		For contraindicated PDE5 enzyme inhibitors, [see Contraindications (4)].
sildenafil, tadalafil, vardenafil	↑ sildenafil ↑ tadalafil ↑ vardenafil	Increases in PDE5 inhibitor concentrations are expected, and may result in an increase in adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of REVATIO^® (sildenafil) or ADCIRCA^® (tadalafil) for the treatment of pulmonary arterial hypertension (PAH) is contraindicated with VICTRELIS [see Contraindications (4)]. Use of PDE5 inhibitors for erectile dysfunction: Use with caution in combination with VICTRELIS with increased monitoring for PDE5 inhibitor-associated adverse events. Do not exceed the following doses: Sildenafil: 25 mg every 48 hours Tadalafil: 10 mg every 72 hours Vardenafil: 2.5 mg every 24 hours
Proton Pump Inhibitor: omeprazole	↔ omeprazole	No dose adjustment of omeprazole or VICTRELIS is recommended.
Sedative/hypnotics:		For contraindicated sedatives/hypnotics, [see Contraindications (4)].
alprazolam; IV midazolam	↑ midazolam ↑ alprazolam	Close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised during coadministration of VICTRELIS. A lower dose of IV midazolam or alprazolam should be considered.

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug Name	Effect on Concentration of Lopinavir or Concomitant Drug	Clinical Comments
HIV-1 Antiviral Agents
HIV-1 Protease Inhibitor: fosamprenavir/ritonavir	↓ amprenavir ↓ lopinavir	An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: indinavir*	↑ indinavir	Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor: nelfinavir*	↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir	KALETRA once daily in combination with nelfinavir is not recommended [see Dosage and Administration (2)].
HIV-1 Protease Inhibitor: ritonavir*	↑ lopinavir	Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: saquinavir	↑ saquinavir	The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor: tipranavir*	↓ lopinavir	Co-administration with tipranavir (500 mg twice daily) and ritonavir (200 mg twice daily) is not recommended.
HIV CCR5 – Antagonist: maraviroc*	↑ maraviroc	When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for maraviroc.
Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz, nevirapine	↓ lopinavir	Increase the dose of KALETRA tablets to 500/125 mg when KALETRA tablet is co-administered with efavirenz or nevirapine. KALETRA once daily in combination with efavirenz or nevirapine is not recommended [see Dosage and Administration (2)].
Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine	↑ lopinavir	Appropriate doses of the combination with respect to safety and efficacy have not been established.
Nucleoside Reverse Transcriptase Inhibitor: didanosine		KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).
Nucleoside Reverse Transcriptase Inhibitor: tenofovir disoproxil fumarate*	↑ tenofovir	Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitors: abacavir zidovudine	↓ abacavir ↓ zidovudine	The clinical significance of this potential interaction is unknown.
Other Agents
Antiarrhythmics e.g. amiodarone, bepridil, lidocaine (systemic), quinidine	↑ antiarrhythmics	For contraindicated antiarrhythmics, [see Contraindications (4)]. Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.
Anticancer Agents: vincristine, vinblastine, dasatinib, nilotinib, venetoclax	↑ anticancer agents	For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions. Coadministration of venetoclax and KALETRA may increase the risk of tumor lysis syndrome. Refer to the venetoclax prescribing information for dosing instructions.
Anticoagulants: warfarin, rivaroxaban	↑↓ warfarin ↑ rivaroxaban	Concentrations of warfarin may be affected. Initial frequent monitoring of the INR during KALETRA and warfarin co-administration is recommended. Avoid concomitant use of rivaroxaban and KALETRA. Co-administration of KALETRA and rivaroxaban may lead to increased risk of bleeding.
Anticonvulsants: carbamazepine, phenobarbital, phenytoin	↓ lopinavir ↓ phenytoin	KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA once daily in combination with carbamazepine, phenobarbital, or phenytoin is not recommended. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
Anticonvulsants: lamotrigine, valproate	↓ lamotrigine ↓ or ↔ valproate	A dose increase of lamotrigine or valproate may be needed when co-administered with KALETRA and therapeutic concentration monitoring for lamotrigine may be indicated; particularly during dosage adjustments.
Antidepressant: bupropion	↓ bupropion ↓ active metabolite, hydroxybupropion	Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant: trazodone	↑ trazodone	Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. A lower dose of trazodone should be considered.
Anti-infective: clarithromycin	↑ clarithromycin	For patients with renal impairment, adjust clarithromycin dose as follows: For patients on KALETRA with CL_CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients on KALETRA with CL_CR < 30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary.
Antifungals: ketoconazole, itraconazole, voriconazole isavuconazonium sulfate	↑ ketoconazole ↑ itraconazole ↓ voriconazole ↑ isavuconazonium	High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended. The coadministration of voriconazole and KALETRA should be avoided unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Isavuconazonium and Kaletra should be coadministered with caution. Alternative antifungal therapies should be considered in these patients.
Anti-gout: colchicine	↑ colchicine	Concomitant administration with colchicine is contraindicated in patients with renal and/or hepatic impairment [see Contraindications (4)]. For patients with normal renal or hepatic function: Treatment of gout flares-co-administration of colchicine in patients on KALETRA: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on KALETRA: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial: bedaquiline	↑ bedaquiline	For contraindicated antimycobacterials, [see Contraindications (4)]. Bedaquiline should only be used with KALETRA if the benefit of co-administration outweighs the risk.
Antimycobacterial: rifabutin*	↑ rifabutin and rifabutin metabolite	Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antiparasitic: atovaquone	↓ atovaquone	Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Antipsychotics: quetiapine	↑ quetiapine	Initiation of KALETRA in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking KALETRA: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
Sedative/hypnotics: parenterally administered midazolam	↑ midazolam	For contraindicated sedative/hypnotics,[see Contraindications (4)]. If KALETRA is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Contraceptive: ethinyl estradiol*	↓ ethinyl estradiol	Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.
Systemic/Inhaled/ Nasal/Ophthalmic Corticosteroids: e.g., betamethasone budesonide ciclesonide dexamethasone fluticasone methylprednisolone mometasone prednisone triamcinolone	↓ lopinavir ↑ glucocorticoids	Coadministration with oral dexamethasone or other systemic corticosteroids that induce CYP3A may result in loss of therapeutic effect and development of resistance to lopinavir. Consider alternative corticosteroids. Coadministration with corticosteroids whose exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression. Alternative corticosteroids including beclomethasone and prednisolone (whose PK and/or PD are less affected by strong CYP3A inhibitors relative to other studied steroids) should be considered, particularly for long-term use.
Dihydropyridine Calcium Channel Blockers: e.g. felodipine, nifedipine, nicardipine	↑ dihydropyridine calcium channel blockers	Clinical monitoring of patients is recommended and a dose reduction of the dihydropyridine calcium channel blocker may be considered.
Disulfiram/metronidazole		KALETRA oral solution contains ethanol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Endothelin Receptor Antagonists: bosentan	↑ bosentan	Co-administration of bosentan in patients on KALETRA: In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Co-administration of KALETRA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA. After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Hepatitis C direct acting antivirals: boceprevir* simeprevir ombitasvir/paritaprevir/ ritonavir and dasabuvir*	↓ lopinavir ↓ boceprevir ↓ ritonavir ↑ simeprevir ↑ ombitasvir ↑ paritaprevir ↑ ritonavir ↔ dasabuvir	For contraindicated hepatitis C direct acting antivirals, [see Contraindications (4)]. It is not recommended to co-administer KALETRA and boceprevir, simeprevir, or ombitasvir/paritaprevir/ritonavir and dasabuvir.
HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin	↑ atorvastatin ↑ rosuvastatin	For contraindicated HMG-CoA reductase inhibitors, [see Contraindications (4)]. Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day.
Immunosuppressants: e.g. cyclosporine, tacrolimus, sirolimus	↑ immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Long-acting beta-adrenoceptor Agonist: salmeterol	↑ salmeterol	Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesics: methadone,* fentanyl	↓ methadone ↑ fentanyl	Dosage of methadone may need to be increased when co-administered with KALETRA. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA.
PDE5 inhibitors: avanafil, sildenafil, tadalafil, vardenafil	↑ avanafil ↑ sildenafil ↑ tadalafil ↑ vardenafil	For contraindicated PDE5 inhibitors, [see Contraindications (4)]. Do not use KALETRA with avanafil because a safe and effective avanafil dosage regimen has not been established. Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio^®) is contraindicated [see Contraindications (4)]. The following dose adjustments are recommended for use of tadalafil (Adcirca^®) with KALETRA: Co-administration of ADCIRCA in patients on KALETRA: In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Co-administration of KALETRA in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: It is recommended not to exceed the following doses: • Sildenafil: 25 mg every 48 hours • Tadalafil: 10 mg every 72 hours • Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events.
* see Clinical Pharmacology (12.3) for magnitude of interaction.

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Classes of Drugs
5-lipoxygenase Inhibitor Adrenergic Stimulants, Central Alcohol Abuse Reduction Preparations Analgesics Anesthetics, Inhalation Antiandrogen Antiarrhythmics† Antibiotics† Aminoglycosides (oral) Cephalosporins, parenteral Macrolides Miscellaneous Penicillins, intravenous, high dose Quinolones (fluoroquinolones) Sulfonamides, long acting Tetracyclines Anticoagulants Anticonvulsants† Antidepressants† Antimalarial Agents Antineoplastics† Antiparasitic/Antimicrobials	Antiplatelet Drugs/Effects Antithyroid Drugs† Beta-Adrenergic Blockers Cholelitholytic Agents Diabetes Agents, Oral Diuretics† Fungal Medications, Intravaginal, Systemic† Gastric Acidity and Peptic Ulcer Agents† Gastrointestinal Prokinetic Agents Ulcerative Colitis Agents Gout Treatment Agents Hemorrheologic Agents Hepatotoxic Drugs Hyperglycemic Agents Hypertensive Emergency Agents Hypnotics† Hypolipidemics† Bile Acid-Binding Resins† Fibric Acid Derivatives HMG-CoA Reductase Inhibitors†	Leukotriene Receptor Antagonist Monoamine Oxidase Inhibitors Narcotics, prolonged Nonsteroidal Anti- Inflammatory Agents Proton Pump Inhibitors Psychostimulants Pyrazolones Salicylates Selective Serotonin Reuptake Inhibitors Steroids, Adrenocortical† Steroids, Anabolic (17-Alkyl Testosterone Derivatives) Thrombolytics Thyroid Drugs Tuberculosis Agents† Uricosuric Agents Vaccines Vitamins†

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Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine, danazol	Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem	Do not exceed 40 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2 fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, and nefazodone), Erythromycin	Contraindicated with lovastatin
Gemfibrozil, cyclosporine	Avoid with lovastatin
Danazol, diltiazem, dronedarone, verapamil	Do not exceed 20 mg lovastatin daily
Amiodarone	Do not exceed 40 mg lovastatin daily
Grapefruit juice	Avoid grapefruit juice

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Table 6 Clinically Important Drug Interactions
Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Tricyclic antidepressants	Increase blood pressure and may counteract clonidine’s hypotensive effects	Monitor blood pressure and adjust as needed
Antihypertensive drugs	Potentiate clonidine’s hypotensive effects	Monitor blood pressure and adjust as needed
CNS depressants	Potentiate sedating effects	Avoid use
Drugs that affect sinus node function or AV node conduction (e.g., digitalis, calcium channel blockers, beta blockers)	Potentiate bradycardia and risk of AV block	Avoid use

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Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs that Interfere with Hemostasis
Clinical Impact :	Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention :	Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions ( 5 . 11)].
Aspirin
Clinical Impact :	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions ( 5 . 2)].
Intervention :	Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions ( 5 . 11)]. Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors , Angiotensin Receptor Blockers , or Beta - Blockers
Clinical Impact :	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention :	During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions ( 5 . 6 )]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact :	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention :	During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions ( 5 . 6)].
Lithium
Clinical Impact :	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology ( 12 . 3)].
Intervention :	During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact :	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention :	During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact :	Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention :	During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact :	Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions ( 5 . 2)].
Intervention :	The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact :	Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention :	During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.

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Table 1: Drugs that may have their plasma concentrations increased by itraconazole
Drug Class	Contraindicated	Not Recommended	Use with Caution	Comments
	Under no circumstances is the drug to be coadministered with itraconazole , and up to two weeks after discontinuation of treatment with itraconazole .	It is recommended that the use of the drug be avoided during and up to two weeks after discontinuation of treatment with itraconazole , unless the benefits outweigh the potentially increased risks of side effects. If coadministration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of the interacting drug is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured. The label of the coadministered drug should be consulted for information on dose adjustment and adverse effects.	Careful monitoring is recommended when the drug is coadministered with itraconazole . Upon coadministration , it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of the interacting drug, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured. The label of the coadministered drug should be consulted for information on dose adjustment and adverse effects.
Alpha Blockers		tamsulosin
Analgesics	methadone		alfentanil, buprenorphine IV and sublingual, fentanyl, oxycodone, sufentanil	Methadone: The potential increase in plasma concentrations of methadone when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation and torsade de pointes.
				Fentanyl: The potential increase in plasma concentrations of fentanyl when coadministered with itraconazole may increase the risk of potentially fatal respiratory depression.
				Sufentanil : No human pharmacokinetic data of an interaction with itraconazole are available. In vitro data suggest that sufentanil is metabolized by CYP3A4 and so potentially increased sufentanil plasma concentrations would be expected when coadministered with itraconazole.
Antiarrhythmics	disopyramide, dofetilide, dronedarone, quinidine		digoxin	Disopyramide , dofetilide , dronedarone , quinidine: The potential increase in plasma concentrations of these drugs when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation.
Antibacterials	telithromycin, in subjects with severe renal impairment or severe hepatic impairment	rifabutin	telithromycin	Telithromycin : The potential increase in plasma concentrations of telithromycin in subjects with severe renal impairment or severe hepatic impairment, when coadministered with itraconazole may increase the risk of serious cardiovascular events including QT prolongation and torsade de pointes. Rifabutin : See also under 'Drugs that may decrease itraconazole plasma concentrations'.
Anticoagulants and Antiplatelet Drugs	ticagrelor	apixaban, rivaroxaban	coumarins, cilostazol, dabigatran	Ticagrelor : The potential increase in plasma concentrations of ticagrelor may increase the risk of bleeding. Coumarins : Itraconazole may enhance the anticoagulant effect of coumarin-like drugs, such as warfarin.
Anticonvulsants		carbamazepine		Carbamazepine: In vivo studies have demonstrated an increase in plasma carbamazepine concentrations in subjects concomitantly receiving ketoconazole. Although there are no data regarding the effect of itraconazole on carbamazepine metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of itraconazole and carbamazepine may inhibit the metabolism of carbamazepine. See also under 'Drugs that may decrease itraconazole plasma concentrations'.
Antidiabetics			repaglinide, saxagliptin
Antihelmintics and Antiprotozoals			praziquantel
Antimigraine Drugs	ergot alkaloids, such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine)		eletriptan	Ergot Alkaloids: The potential increase in plasma concentrations of ergot alkaloids when coadministered with itraconazole may increase the risk of ergotism, i.e., a risk for vasospasm potentially leading to cerebral ischemia and/or ischemia of the extremities.
Antineoplastics	irinotecan	axitnib, dabrafenib, dasatinib, ibrutinib, nilotinib, sunitinib	bortezomib, busulphan, docetaxel, erlotinib, imatinib, ixabepilone, lapatinib, ponatinib, trimetrexate, vinca alkaloids	Irinotecan: The potential increase in plasma concentrations of irinotecan when coadministered with itraconazole may increase the risk of potentially fatal adverse events.
Antipsychotics, Anxiolytics and Hypnotics	lurasidone, oral midazolam, pimozide, triazolam		alprazolam, aripiprazole, buspirone, diazepam, haloperidol, midazolam IV, perospirone, quetiapine, ramelteon, risperidone	Midazolam, triazolam: Coadministration of itraconazole and oral midazolam, or triazolam may cause several-fold increases in plasma concentrations of these drugs. This may potentiate and prolong hypnotic and sedative effects, especially with repeated dosing or chronic administration of these agents.
				Pimozide : The potential increase in plasma concentrations of pimozide when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation and torsade de pointes.
Antivirals		simeprevir	maraviroc, indinavir, ritonavir, saquinavir	Indinavir , ritonavir: See also under 'Drugs that may increase itraconazole plasma concentrations'.
Beta Blockers			nadolol
Calcium Channel Blockers	felodipine, nisoldipine		other dihydropyridines, verapamil	Calcium channel blockers can have a negative inotropic effect which may be additive to those of itraconazole. The potential increase in plasma concentrations of calcium channel blockers when co-administered with itraconazole may increase the risk of congestive heart failure. Dihydropyridines : Concomitant administration of itraconazole may cause several-fold increases in plasma concentrations of dihydropyridines. Edema has been reported in patients concomitantly receiving itraconazole and dihydropyridine calcium channel blockers.
Cardiovascular Drugs, Miscellaneous	ranolazine	aliskiren, sildenafil, for the treatment of pulmonary hypertension	bosentan, riociguat	Ranolazine : The potential increase in plasma concentrations of ranolazine when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation.
Diuretics	eplerenone			Eplerenone : The potential increase in plasma concentrations of eplerenone when coadministered with itraconazole may increase the risk of hyperkalemia and hypotension.
Gastrointestinal Drugs	cisapride		aprepitant	Cisapride : The potential increase in plasma concentrations of cisapride when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation.
Immunosuppressants		everolimus, temsirolimus	budesonide, ciclesonide, cyclosporine, dexamethasone, fluticasone, methylprednisolone, rapamycin (also known as sirolimus), tacrolimus
Lipid Regulating Drugs	lovastatin, simvastatin		atorvastatin	The potential increase in plasma concentrations of atorvastatin, lovastatin, and simvastatin when coadministered with itraconazole may increase the risk of skeletal muscle toxicity, including rhabdomyolysis.
Respiratory Drugs		salmeterol
Urological Drugs	fesoterodine, in subjects with moderate to severe renal impairment, or moderate to severe hepatic impairment, solifenacin, in subjects with severe renal impairment or moderate to severe hepatic impairment	darifenacin, vardenafil	fesoterodine, oxybutynin, sildenafil, for the treatment of erectile dysfunction, solifenacin, tadalafil, tolterodine	Fesoterodine : The potential increase in plasma concentrations of the fesoterodine active metabolite may be greater in subjects with moderate to severe renal impairment, or moderate to severe hepatic impairment, which may lead to an increased risk of adverse reactions. Solifenacin: The potential increase in plasma concentrations of solifenacin in subjects with severe renal impairment or moderate to severe hepatic impairment, when coadministered with itraconazole may increase the risk of serious cardiovascular events including QT prolongation.
Other	colchicine, in subjects with renal or hepatic impairment	colchicine, conivaptan, tolvaptan	cinacalcet	Colchicine: The potential increase in plasma concentrations of colchicine when coadministered with itraconazole may increase the risk of potentially fatal adverse events. Conivaptan and Tolvaptan : A safe and effective dose of either conivaptan or tolvaptan has not been established when coadministered with itraconazole.

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Table 3: Clinically Significant Drug Interactions with ADDYI
Alcohol
Clinical Implications	The concomitant use of ADDYI with alcohol increased the risk of hypotension, syncope, and CNS depression compared to the use of ADDYI alone or alcohol alone [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2)].
Preventing or Managing DI	The concomitant use of ADDYI with alcohol is contraindicated.
Other CNS Depressants
Examples	Diphenhydramine, opioids, hypnotics, benzodiazepines
Clinical Implications	The concomitant use of ADDYI with CNS depressants may increase the risk of CNS depression (e.g., somnolence) compared to the use of ADDYI alone.
Preventing or Managing DI	Discuss the concomitant use of other CNS depressants with the patient when prescribing ADDYI.
Moderate or Strong CYP3A4 Inhibitors
Examples of strong CYP3A4 inhibitors	Ketoconazole, itraconazole, posaconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, boceprevir, telaprevir, telithromycin and conivaptan
Examples of moderate CYP3A4 inhibitors	Amprenavir, atazanavir, ciprofloxacin, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil, and grapefruit juice
Clinical Implications	The concomitant use of ADDYI with moderate or strong CYP3A4 inhibitors increases flibanserin exposure compared to the use of ADDYI alone. The risk of hypotension and syncope is increased with concomitant use of ADDYI and moderate or strong CYP3A4 inhibitors [see Warnings and Precautions (5.3), Adverse Reactions (6.1), and Clinical Pharmacology (12.3)].
Preventing or Managing DI	The concomitant use of ADDYI with moderate or strong CYP3A4 inhibitors is contraindicated.
Weak CYP3A4 Inhibitors
Examples	Oral contraceptives, cimetidine, fluoxetine, ginkgo, ranitidine
Clinical Implications	The concomitant use of ADDYI with multiple weak CYP3A4 inhibitors may increase the risk of adverse reactions.
Preventing or Managing DI	Discuss the use of multiple weak CYP3A4 inhibitors with the patient when prescribing ADDYI.
Strong CYP2C19 Inhibitors
Examples	Proton pump inhibitors, selective serotonin reuptake inhibitors, benzodiazepines, antifungals
Clinical Implications	The concomitant use of ADDYI with strong CYP2C19 inhibitors may increase flibanserin exposure which may increase the risk of hypotension, syncope, and CNS depression.
Preventing or Managing DI	Discuss the use of a strong CYP2C19 inhibitor with the patient when prescribing ADDYI.
CYP3A4 Inducers
Examples	Carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapetine, St. John's Wort
Clinical Implications	The concomitant use of ADDYI with CYP3A4 inducers substantially decreases flibanserin exposure compared to the use of ADDYI alone.
Preventing or Managing DI	The concomitant use of ADDYI with CYP3A4 inducers is not recommended.
Digoxin or Other P-glycoprotein Substrates
Examples	Digoxin, sirolimus
Clinical Implications	The concomitant use of ADDYI with digoxin, a drug that is transported by P-glycoprotein (P-gp), increases the digoxin concentration [see Clinical Pharmacology (12.3)]. This may lead to digoxin toxicity.
Preventing or Managing DI	Increase monitoring of concentrations of drugs transported by P-gp that have a narrow therapeutic index (e.g., digoxin).

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Inhibitors of CYP3A4
Clinical Impact:	The concomitant use of fentanyl transdermal system and CYP3A4 inhibitors can increase the plasma concentration of fentanyl, resulting in increased or prolonged opioid effects particularly when an inhibitor is added after a stable dose of fentanyl transdermal system is achieved [see Warnings and Precautions (5.5)]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl transdermal system plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to fentanyl.
Intervention:	If concomitant use is necessary, consider dosage reduction of fentanyl transdermal system until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the fentanyl transdermal system dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir), grape fruit juice
CYP3A4 Inducers
Clinical Impact:	The concomitant use of fentanyl transdermal system and CYP3A4 inducers can decrease the plasma concentration of fentanyl [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to fentanyl [see Warnings and Precautions (5.5)]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention:	If concomitant use is necessary, consider increasing the fentanyl transdermal system dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider fentanyl transdermal system dosage reduction and monitor for signs of respiratory depression.
Examples:	Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.7)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions 5.10].
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue fentanyl transdermal system if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.10)] or opioid toxicity (e.g., respiratory depression, coma).
Intervention:	The use of fentanyl transdermal system is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of fentanyl transdermal system and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Fentanyl transdermal system may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of fentanyl transdermal system and/or the muscle relaxant as necessary.

Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl transdermal system is used concomitantly with anticholinergic drugs.

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Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)	VIAGRA 50 mg (95% CI)
Supine	9.08 (5.48, 12.68)
Standing	11.62 (7.34, 15.90)

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Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (C_max and AUC _τ after 200 mg q12h)	Recommendations for Voriconazole Dosage Adjustment/Comments
Rifampin* and Rifabutin* (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (400 mg q24h) (CYP450 Induction) Efavirenz (300 mg q24h) (CYP450 Induction)	Significantly Reduced Slight Decrease in AUC_τ	Contraindicated When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High dose Ritonavir (400 mg q12h) (CYP450 Induction) Low dose Ritonavir (100 mg q12h) (CYP450 Induction)	Significantly Reduced Reduced	Contraindicated Coadministration of voriconazole and low dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Phenytoin* (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John’s Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives** containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole** (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIs*** (CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure) A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to voriconazole Careful assessment of voriconazole effectiveness

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Table 4. Drugs That May Alter Hepatic Metabolism of T4 (Hypothyroidism)
Potential impact: Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased SYNTHROID requirements.
Drug or Drug Class	Effect
Phenobarbital Rifampin	Phenobarbital has been shown to reduce the response to thyroxine. Phenobarbital increases L-thyroxine metabolism by inducing uridine 5’-diphospho-glucuronosyltransferase (UGT) and leads to a lower T4 serum levels. Changes in thyroid status may occur if barbiturates are added or withdrawn from patients being treated for hypothyroidism. Rifampin has been shown to accelerate the metabolism of levothyroxine.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄ . Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³ I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Concomitant Drug	Effect onConcentration ofLamotrigine orConcomitant Drug	Clinical Comment
Estrogen-containing oralcontraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine concentrationsapproximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepineand carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentrationapproximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUCapproximately 32%.

Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold.There are conflicting study resultsregarding effect of lamotrigine onvalproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change invalproate concentrations in controlled clinical trials in patients with epilepsy.

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Oral hypoglycemics	Tofacitinib	Cyclophosphamide
Coumarin-type anticoagulants	Triazolam	Fentanyl
Phenytoin	Oral contraceptives	Halofantrine
Cyclosporine	Pimozide	HMG-CoA reductase inhibitors
Rifampin	Quinidine	Losartan
Theophylline	Hydrochlorothiazide	Methadone
Terfenadine	Alfentanil	Non-steroidal anti-inflammatory drugs
Cisapride	Amitriptyline, nortriptyline	Prednisone
Astemizole	Amphotericin B	Saquinavir
Rifabutin	Azithromycin	Sirolimus
Voriconazole	Carbamazepine	Vinca alkaloids
Tacrolimus	Calcium channel blockers	Vitamin A
Short-acting benzodiazepines	Celecoxib	Zidovudine

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Classes of Drugs
5-lipoxygenase Inhibitor Adrenergic Stimulants, Central Alcohol Abuse Reduction Preparations Analgesics Anesthetics, Inhalation Antiandrogen Antiarrhythmics† Antibiotics† Aminoglycosides (oral) Cephalosporins, parenteral Macrolides Miscellaneous Penicillins, intravenous, high dose Quinolones (fluoroquinolones) Sulfonamides, long acting Tetracyclines Anticoagulants Anticonvulsants† Antidepressants† Antimalarial Agents Antineoplastics† Antiparasitic/Antimicrobials	Antiplatelet Drugs/Effects Antithyroid Drugs† Beta-Adrenergic Blockers Cholelitholytic Agents Diabetes Agents, Oral Diuretics† Fungal Medications, Intravaginal, Systemic† Gastric Acidity and Peptic Ulcer Agents† Gastrointestinal Prokinetic Agents Ulcerative Colitis Agents Gout Treatment Agents Hemorrheologic Agents Hepatotoxic Drugs Hyperglycemic Agents Hypertensive Emergency Agents Hypnotics† Hypolipidemics† Bile Acid-Binding Resins† Fibric Acid Derivatives HMG-CoA Reductase Inhibitors†	Leukotriene Receptor Antagonist Monoamine Oxidase Inhibitors Narcotics, prolonged Nonsteroidal Anti- Inflammatory Agents Proton Pump Inhibitors Psychostimulants Pyrazolones Salicylates Selective Serotonin Reuptake Inhibitors Steroids, Adrenocortical† Steroids, Anabolic (17-Alkyl Testosterone Derivatives) Thrombolytics Thyroid Drugs Tuberculosis Agents† Uricosuric Agents Vaccines Vitamins†

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Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Table 2: Rifabutin Interaction Studies
↑ indicates increase; ↓ indicates decrease; ↔ indicates no significant change
QD-once daily; BID-twice daily; TID – thrice daily
ND -No Data
AUC -Area under the Concentration vs. Time Curve; C _max -Maximum serum concentration
^acompared to rifabutin 300 mg QD alone
^bcompared to historical control (fosamprenavir/ritonavir 700/100 mg BID)
^calso taking zidovudine 500 mg QD
^dcompared to rifabutin 150 mg QD alone
^ecompared to rifabutin 300 mg QD alone
^fdata from a case report
^gcompared to voriconazole 200 mg BID alone
Coadministered drug	Dosing regimen of coadministered drug	Dosing regimen of rifabutin	Study population (n)	Effect on rifabutin	Effect on coadministered drug	Recommendation
ANTIVIRALS
Amprenavir	1200 mg BID x 10 days	300 mg QD x 10 days	Healthy male subjects (6)	↑ AUC by 193%, ↑ C _maxby 119%	↔	Reduce rifabutin dose by at least 50%. Monitor closely for adverse reactions.
Delavirdine	400 mg TID	300 mg QD	HIV-infected patients (7)	↑ AUC by 230%, ↑ C _maxby 128%	↓ AUC by 80%, ↓ Cmax by 75%, ↓ C _minby 17%	CONTRAINDICATED
Didanosine	167 or 250 mg BID x 12 days	300 or 600 mg QD x 1	HIV-infected patients (11)	↔	↔
Fosamprenavir/ ritonavir	700 mg BID plus ritonavir 100 mg BID x 2 weeks	150 mg every other day x 2 weeks	Healthy subjects (15)	↔ AUC ^a ↓ C _max by 15%	↑ AUC by 35% ^b, ↑ C _max by 36%, ↑ C _min by 36%	Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with fosamprenavir/ ritonavir combination.
Indinavir	800 mg TID x 10 days	300 mg QD x 10 days	Healthy subjects (10)	↑ AUC by 173%, ↑ C _max by 134%	↓ AUC by 34%, ↓ C _max by 25%, ↓ C _min by 39%	Reduce rifabutin dose by 50%, and increase indinavir dose from 800 mg to 1000 mg TID.
Lopinavir/ ritonavir	400/100 mg BID x 20 days	150 mg QD x 10 days	Healthy subjects (14)	↑ AUC by 203% ^c ↓ C _max by 112%	↔	Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed.
Saquinavir/ ritonavir	1000/100 mg BID x 14 or 22 days	150 mg every 3 days X 21 to 22 days	Healthy subjects	↑ AUC by 53% ^d ↑ C _max by 88% (n=11)	↓ AUC by 13%, ↓ C _max by 15%, (n=19)	Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with saquinavir/ritonavir combination. Monitor closely for adverse reactions.
Ritonavir	500 mg BID x 10 days	150 mg QD x 16 days	Healthy subjects (5)	↑ AUC by 300%, ↑ C _max by 150%	ND	Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed.
Tipranavir/ ritonavir	500/200 BID X 15 doses	150 mg single dose	Healthy subjects (20)	↑ AUC by 190%, ↑ C _max by 70%	↔	Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with tipranavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed.
Nelfinavir	1250 mg BID x 7 to 8 days	150 mg QD x 8 days	HIV-infected patients (11)	↑ AUC by 83%, ^e ↑ C _max by 19%	↔	Reduce rifabutin dose by 50% (to 150 mg QD) and increase the nelfinavir dose to 1250 mg BID
Zidovudine	100 or 200 mg q4h	300 or 450 mg QD	HIV-infected patients (16)	↔	↓ AUC by 32%, ↓ C _max by 48%	Because zidovudine levels remained within the therapeutic range during coadministration of rifabutin, dosage adjustments are not necessary.
ANTIFUNGALS
Fluconazole	200 mg QD x 2 weeks	300 mg QD x 2 weeks	HIV-infected patients (12)	↑ AUC by 82%, ↑C _max by 88%	↔	Monitor for rifabutin associated adverse events. Reduce rifabutin dose or suspend rifabutin use if toxicity is suspected.
Posaconazole	200 mg QD x 10 days	300 mg QD x 17 days	Healthy subjects (8)	↑ AUC by 72%, ↑ C _max by 31%	↓ AUC by 49%, ↓ C _max by 43%	If co-administration of these two drugs cannot be avoided, patients should be monitored for adverse events associated with rifabutin administration, and lack of posaconazole efficacy.
Itraconazole	200 mg QD	300 mg QD	HIV-Infected patients (6)	↑ ^f	↓ AUC by 70%, ↓ C _max by 75%	If co-administration of these two drugs cannot be avoided, patients should be monitored for adverse events associated with rifabutin administration, and lack of itraconazole efficacy. In a separate study, one case of uveitis was associated with increased serum rifabutin levels following coadministration of rifabutin (300 mg QD) with itraconazole (600 to 900 mg QD).
Voriconazole	400 mg BID x 7 days (maintenance dose)	300 mg QD x 7 days	Healthy male subjects (12)	↑ AUC by 331%, ↑ C _max by 195%	↑ AUC by ~100%, ↑ C _max by ~100% ^g	CONTRAINDICATED
ANTI-PCP (Pneumocystis carinii pneumonia)
Dapsone	50 mg QD	300 mg QD	HIV-infected patients (16)	ND	↓ AUC by 27 to 40%
Sulfamethoxazole -Trimethoprim	800/160 mg	300 mg QD	HIV-infected patients (12)	↔	↓ AUC by 15 to 20%
ANTI-MAC (Mycobacterium avium intracellulare complex)
Azithromycin	500 mg QD x 1 day, then 250 mg QD x 9 days	300 mg QD	Healthy subjects (6)	↔	↔
Clarithromycin	500 mg BID	300 mg QD	HIV-infected patients (12)	↑ AUC by 75%	↓ AUC by 50%	Monitor for rifabutin associated adverse events. Reduce dose or suspend use of rifabutin if toxicity is suspected. Alternative treatment for clarithromycin should be considered when treating patients receiving rifabutin
ANTI-TB (Tuberculosis)
Ethambutol	1200 mg	300 mg QD X 7 days	Healthy subjects(10)	ND	↔
Isoniazid	300 mg	300 mg QD X 7 days	Healthy subjects (6)	ND	↔
OTHER
Methadone	20 to 100 mg QD	300 mg QD X 13 days	HIV-infected patients (24)	ND	↔
Ethinylestradiol (EE)/ Norethindrone (NE)	35 mg EE / 1 mg NE X 21 days	300 mg QD X 10 days	Healthy female subjects (22)	ND	EE: ↓ AUC by 35%, ↓ C _max by 20% NE: ↓ AUC by 46%	Patients should be advised to use additional or alternative methods of contraception.
Theophylline	5 mg/kg	300 mg X 14 days	Healthy subjects (11)	ND	↔

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Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
*Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	C _max
Enzyme (CYP2D6) inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not Needed

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Table 3: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in BPH patients on stable alpha-blocker therapy with tamsulosin 0.4 or 0.8 mg daily (Study 2)
	Vardenafil 10 mg Placebo-subtracted	Vardenafil 20 mg Placebo-subtracted
Standing SBP	-4 (-6.8, -0.3)	-4 (-6.8, -1.4)
Supine SBP	-5 (-8.2, -0.8)	-4 (-6.3, -1.8)

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Drug	Description
Heparin	Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients
Pyrazinamide	Inhibits pyrazinamide-induced hyperuricemia
Uricosuric Agents	Effect of probenecid, sulfinpyrazone and phenylbutazone inhibited

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Factors	Dosage Adjustment of Aripiprazole tablets
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors	Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double usual dose over 1 to 2 weeks

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Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.9)].
Benzodiazepines (e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.9)]	Monitor sedation and blood pressure. Adjust dose accordingly.

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Bleeding times
Clinical Impact:	Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention:	This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact:	The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention:	Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact:	Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention:	This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.

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Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Antibiotics	Anticonvulsants	Other Drugs/Dietary Supplements
nafcillin rifampin	carbamazepine oxcarbazepine phenobarbital phenytoin	bosentan octreotide orlistat sulfinpyrazone St. John's Wort terbinafine ticlopidine

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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^aShould be administered at least 4 hours prior to WELCHOL
^bNo significant alteration of warfarin drug levels with warfarin and WELCHOL coadministration in an in vivo study which did not evaluate warfarin pharmacodynamics (INR). [See Post-marketing Experience (6.2)]
^c Cyclosporine levels should be monitored and, based on theoretical grounds, cyclosporine should be administered at least 4 hours prior to WELCHOL.
^dPatients receiving concomitant metformin ER and colesevelam should be monitored for clinical response as is usual for the use of anti-diabetes drugs.
Table 4 Drugs Tested in In Vitro Binding or In Vivo Drug Interaction Testing or With Post-Marketing Reports
Drugs with a known interaction with colesevelam: Decrease in exposure of coadministered drug	cyclosporine^c, glimepiride^a, glipizide^a, glyburide^a, levothyroxine^a, olmesartan medoxomil^a, and oral contraceptives containing ethinyl estradiol and norethindrone^a
Drugs with a known interaction with colesevelam: Increase in exposure of coadministered drug	metformin extended release (ER)^d
Drug(s) with postmarketing reports consistent with potential drug-drug interactions when coadministered with WELCHOL	phenytoin^a, warfarin^b
Drugs that do not interact with colesevelam based on in vitro or in vivo testing	aspirin, atenolol, cephalexin, ciprofloxacin, digoxin, enalapril, fenofibrate, lovastatin, metformin, metoprolol, phenytoin^a, pioglitazone, rosiglitazone, quinidine, repaglinide, sitagliptin, valproic acid, verapamil, warfarin^b

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Substance	Average Duration of Effect
Anti-thyroid drugs e.g., carbimazole, propylthiouracil	5 days
Natural or synthetic thyroid hormone e.g., thyroxine tri-iodothyronine	4 weeks 2 weeks
Iodine-containing medications e.g., amiodarone expectorants, vitamins	4 weeks 2 weeks
Topical iodide	1-9 months
X-ray contrast agents iodine-containing agents	Up to 1 year
Other drugs anticoagulants, antihistamines corticosteroids, sulfonamides tolbutamide, perchlorate phenylbutazone lithium	1 week 1 week 1 week 1-2 weeks 4 weeks

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Drugs that Affect Renal Function	A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics	Dofetilide	Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
	Sotalol	Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
	Dronedarone	Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog	Teriparatide	Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement	Thyroid	Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics	Epinephrine Norepinephrine Dopamine	Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents	Succinylcholine	May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements	Calcium	If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers		Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of this product. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Table 7: Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]
^* Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects ^ Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects ^* Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30-100 mg q24h) ^** Non-Steroidal Anti-Inflammatory Drug ^*** Non-Nucleoside Reverse Transcriptase Inhibitors
Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C_max and AUC_τ)	Recommendations for Drug Dosage Adjustment/Comments
Sirolimus* (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin* (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (400 mg q24h) (CYP3A4 Inhibition) Efavirenz (300 mg q24h) (CYP3A4 Inhibition)	Significantly Increased Slight Increase inAUC_τ	Contraindicated When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h) (CYP3A4 Inhibition) Low-dose Ritonavir (100 mg q12h)	No Significant Effect of Voriconazole on Ritonavir C_max or AUC_τ Slight Decrease in Ritonavir C_max and AUC_τ	Contraindicated because of significant reduction of voriconazole C_max and AUC_τ Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole C_max and AUC_τ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated
Cyclosporine* (CYP3A4 Inhibition)	AUC_τ Significantly Increased; No Significant Effect on C_max	When initiating therapy with voriconazole tablets in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole tablets are discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
Methadone*** (CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazoletablets. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7)]
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole tablet. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see Drug Interactions (7)].
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazoletablets. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7)].
NSAIDs**** including ibuprofen and diclofenac (CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [see Drug Interactions (7)].
Tacrolimus* (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with voriconazole tablets in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazoletablets are discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin* (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)**	Increased	Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin* (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole* (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with voriconazoletablets in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects on Indinavir Exposure In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	No dosage adjustment for indinavir when coadministered with voriconazole tablets Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIs***** (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.
Everolimus (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Concomitant administration of voriconazole and everolimus is not recommended.

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Table 1: Clinically Significant Drug Interactions with Naproxen
Drugs That Interfere with Hemostasis
Clinical Impact:	Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of naproxen tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	Concomitant use of naproxen tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen tablets are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of naproxen tablets and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of naproxen tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention	During concomitant use of naproxen tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of naproxen tablets and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen tablets and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen tablets and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen tablets and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen tablets and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen tablets and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of naproxen tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen tablets are not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen tablets are not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxen tablets are not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen tablets and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:	Patients simultaneously receiving naproxen tablets and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

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Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
Drug Name	Effect on Concentration of Nevirapine or Concomitant Drug	Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir*	↓ Atazanavir ↑ Nevirapine	Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir*	↓Amprenavir ↑Nevirapine	Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir*	↓Amprenavir ↑Nevirapine	No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir*	↓ Indinavir	The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir*	↓Lopinavir	Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra^® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir*	↓ Nelfinavir M8 Metabolite ↓ Nelfinavir C_min	The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/ritonavir	The interaction between nevirapine and saquinavir/ritonavir has not been evaluated	The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz*	↓ Efavirenz	The appropriate doses of these combinations with respect to safety and efficacy have not been established.
Delavirdine Etravirine Rilpivirine		Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.
Hepatitis C Antiviral Agents
Boceprevir	Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine.	Nevirapine and boceprevir should not be coadministered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy.
Telaprevir	Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir.	Nevirapine and telaprevir should not be coadministered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events.
Other Agents
Analgesics: Methadone*	↓Methadone	Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics: Amiodarone, disopyramide, lidocaine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Antibiotics: Clarithromycin*	↓Clarithromycin ↑14-OH clarithromycin	Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium- intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Rifabutin*	↑Rifabutin	Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin*	↓Nevirapine	Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants: Carbamazepine, clonazepam, ethosuximide	Plasma concentrations of nevirapine and the anticonvulsant may be decreased.	Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals: Fluconazole*	↑Nevirapine	Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Ketoconazole*	↓Ketoconazole	Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Itraconazole	↓Itraconazole	Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics: Warfarin	Plasma concentrations may be increased.	Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers: Diltiazem, nifedipine, verapamil	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Cancer chemotherapy: Cyclophosphamide	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Ergot alkaloids: Ergotamine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Motility agents: Cisapride	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Opiate agonists: Fentanyl	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Oral contraceptives: Ethinyl estradiol and Norethindrone*	↓Ethinyl estradiol ↓Norethindrone	Despite lower ethinyl estradiol and norethindrone exposures when coadministered with nevirapine, literature reports suggest that nevirapine has no effect on pregnancy rates among HIV-infected women on combined oral contraceptives. When coadministered with nevirapine, no dose adjustment of ethinyl estradiol or norethindrone is needed when used in combination for contraception. When these oral contraceptives are used for hormonal regulation during nevirapine therapy, the therapeutic effect of the hormonal therapy should be monitored.
* The interaction between nevirapine and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.

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Antibiotics	Anticonvulsants	Other Drugs/Dietary Supplements
nafcillin	carbamazepine	bosentan	terbinafine
rifampin	oxcarbazepine	octreotide	ticlopidine
	phenobarbital	orlistat	St. John's Wort
	phenytoin	sulfinpyrazone

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Bleeding times
Clinical Impact:	Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention:	This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact:	The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention:	Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact:	Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention:	This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.

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DRUG	DESCRIPTION OF INTERACTION
Heparin	Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients.
Pyrazinamide	Inhibits pyrazinamide-induced hyperuricemia.
Uricosuric Agents	Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.

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Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.2, 4, 5.2, 7.1, 7.2, 7.3, 7.4, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol, verapamil, diltiazem	Contraindicated with SIMCOR
Amiodarone, amlodipine, ranolazine	Do not exceed 1000/20 mg SIMCOR daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Inhibitors of CYP2D6
Clinical Impact:	The concomitant use of tramadol hydrochloride and acetaminophen and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride and acetaminophen is achieved. Since M1 is a more potent µ-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease and the M1 plasma concentration will increase which could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, and may cause potentially fatal respiratory depression [see Clinical Pharmacology (12.3)].
Intervention:	If concomitant use of a CYP2D6 inhibitor is necessary, follow patients closely for adverse reactions including opioid withdrawal, seizures and serotonin syndrome. If a CYP2D6 inhibitor is discontinued, consider lowering tramadol hydrochloride and acetaminophen dosage until stable drug effects are achieved. Follow patients closely for adverse events including respiratory depression and sedation.
Examples	Quinidine, fluoxetine, paroxetine and bupropion
Inhibitors of CYP3A4
Clinical Impact:	The concomitant use of tramadol hydrochloride and acetaminophen and CYP3A4 inhibitors can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1. Follow patients closely for increased risk of serious adverse events including seizures and serotonin syndrome, and adverse reactions related to opioid toxicity including potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride and acetaminophen is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy and possibly signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol.
Intervention:	If concomitant use is necessary, consider dosage reduction of tramadol hydrochloride and acetaminophen until stable drug effects are achieved. Follow patients closely for seizures and serotonin syndrome, and signs of respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the tramadol hydrochloride and acetaminophen dosage until stable drug effects are achieved and follow patients for signs and symptoms of opioid withdrawal.
Examples	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact:	The concomitant use of tramadol hydrochloride and acetaminophen and CYP3A4 inducers can decrease the plasma concentration of tramadol [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression, seizures and serotonin syndrome.
Intervention:	If concomitant use is necessary, consider increasing the tramadol hydrochloride and acetaminophen dosage until stable drug effects are achieved. Follow patients for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider tramadol hydrochloride and acetaminophen dosage reduction and monitor for seizures and serotonin syndrome, and signs of sedation and respiratory depression. Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of tramadol hydrochloride and acetaminophen and carbamazepine is not recommended.
Examples:	Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.6)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue tramadol hydrochloride and acetaminophen if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.7)] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
Intervention:	Do not use tramadol hydrochloride and acetaminophen in patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of tramadol hydrochloride and acetaminophen and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Tramadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of tramadol hydrochloride and acetaminophen and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when tramadol hydrochloride and acetaminophen is used concomitantly with anticholinergic drugs.
Digoxin
Clinical Impact:	Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity.
Intervention:	Follow patients for signs of digoxin toxicity and adjust dosage of digoxin as needed.
Warfarin
Clinical Impact:	Post-marketing surveillance of tramadol has revealed rare reports of alteration of warfarin effect, including elevation of prothrombin times.
Intervention:	Monitor the prothrombin time of patients on warfarin for signs of an interaction and adjust the dosage of warfarin as needed.

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Table 5. Drugs That May Decrease Conversion of T4 to T3
Potential impact: Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased.
Drug or Drug Class	Effect
Beta-adrenergic antagonists (e.g., Propranolol > 160 mg/day)	In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change, TSH levels remain normal, and patients are clinically euthyroid. Actions of particular beta-adrenergic antagonists may be impaired when a hypothyroid patient is converted to the euthyroid state.
Glucocorticoids (e.g., Dexamethasone > 4 mg/day)	Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (See above).
Other drugs: Amiodarone	Amiodarone inhibits peripheral conversion of levothyroxine (T4) to triiodothyronine (T3) and may cause isolated biochemical changes (increase in serum free-T4, and decreased or normal free-T3) in clinically euthyroid patients.

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Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Antibiotics	Anticonvulsants	Other Drugs/DietarySupplements
nafcillin	carbamazepine	bosentan	St. John’s Wort
rifampin	oxcarbazepine	octreotide
	phenobarbital	orlistat
	phenytoin	sulfinpyrazone
		terbinafine
		ticlopidine

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Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of aripiprazole tablets with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole tablets alone [seeCLINICALPHARMACOLOGY( 12.3)].	Withconcomitant use of aripiprazole tablets with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole tablets dosage [see DOSAGEANDADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of aripiprazole tablets and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole tablets alone [see CLINICALPHARMACOLOGY (12.3)].	Withconcomitant use of aripiprazole tablets with a strong CYP3A4 inducer, consider increasing the aripiprazole tablets dosage [see DOSAGE ANDADMINISTRATION( 2.7)].
AntihypertensiveDrugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor bloodpressure and adjust dose accordingly [seeWARNINGS AND PRECAUTIONS (5.8)].
Benzodiazepines(e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [seeWARNINGSANDPRECAUTIONS (5.8)]	Monitor sedation and blood pressure. Adjust dose accordingly.

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AED Coadministered	AED Concentration	Topiramate Concentration
a= Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. b= Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. NE = Not Evaluated
Phenytoin	NC or 25% increasea	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxideb	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Table 6: Clinically Significant Drug Interactions with Paricalcitol
CYP3A Inhibitors
Clinical Impact	Paricalcitol is partially metabolized by CYP3A. Hence, exposure of paricalcitol will increase upon coadministration with strong CYP3A inhibitors such as but not limited to: boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole.
Intervention	Dose adjustment of paricalcitol capsules may be necessary. Monitor closely for iPTH and serum calcium concentrations, if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor.
Cholestyramine
Clinical Impact	Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of paricalcitol.
Intervention	Recommend to take paricalcitol capsules at least 1 hour before or 4 to 6 hours after taking cholestyramine (or at as great an interval as possible) to avoid impeding absorption of paricalcitol.
Mineral Oil
Clinical Impact	Mineral oil or other substances that may affect absorption of fat may influence the absorption of paricalcitol.
Intervention	Recommend to take paricalcitol capsules at least 1 hour before or 4 to 6 hours after taking mineral oil (or at as great an interval as possible) to avoid affecting absorption of paricalcitol.

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Table 8: Clinically Significant Drug Interactions with Clarithromycin
Drugs That Are Affected By Clarithromycin
Drug(s) with Pharmacokinetics Affected by Clarithromycin	Recommendation	Comments
Antiarrhythmics: Disopyramide Quinidine Dofetilide Amiodarone Sotalol Procainamide	Not Recommended	Disopyramide, Quinidine: There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs [see Warnings and Precautions (5.3)]. Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine. There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.
Digoxin	Use With Caution	Digoxin: Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are coadministered, inhibition of Pgp by clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range.
Oral Anticoagulants: Warfarin	Use With Caution	Oral anticoagulants: Spontaneous reports in the postmarketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously [see Warnings and Precautions (5.4)].
Antiepileptics: Carbamazepine	Use With Caution	Carbamazepine: Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered. Increased serum concentrations of carbamazepine were observed in clinical trials with clarithromycin. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with carbamazepine.
Antifungals: Itraconazole Fluconazole	Use With Caution No Dose Adjustment	Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly (see also Itraconazole under “Drugs That Affect Clarithromycin” in the table below). Clarithromycin may increase the plasma concentrations of itraconazole. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions. Fluconazole: [see Pharmacokinetics (12.3)]
Anti-Gout Agents: Colchicine (in patients with renal or hepatic impairment) Colchicine (in patients with normal renal and hepatic function)	Contraindicated Use With Caution	Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. The dose of colchicine should be reduced when co-administered with clarithromycin in patients with normal renal and hepatic function [see Contraindications (4.4) and Warnings and Precautions (5.4)].
Antipsychotics: Pimozide Quetiapine	Contraindicated	Pimozide: [See Contraindications (4.2)] Quetiapine: Quetiapine is a substrate for CYP3A4, which is inhibited by clarithromycin. Coadministration with clarithromycin could result in increased quetiapine exposure and possible quetiapine related toxicities. There have been postmarketing reports of somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation during concomitant administration. Refer to quetiapine prescribing information for recommendations on dose reduction if coadministered with CYP3A4 inhibitors such as clarithromycin.
Antispasmodics: Tolterodine (patients deficient in CYP2D6 activity)	Use With Caution	Tolterodine: The primary route of metabolism for tolterodine is via CYP2D6. However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when co-administered with clarithromycin.
Antivirals: Atazanavir Saquinavir (in patients with decreased renal function) Ritonavir Etravirine Maraviroc Boceprevir (in patients with normal renal function) Zidovudine	Use With Caution No Dose Adjustment	Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)]. Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction (see Saquinavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)]. Ritonavir, Etravirine: (see Ritonavir and Etravirine under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)]. Maraviroc: Clarithromycin may result in increases in maraviroc exposures by inhibition of CYP3A metabolism. See Selzentry^® prescribing information for dose recommendation when given with strong CYP3A inhibitors such as clarithromycin. Boceprevir: Both clarithromycin and boceprevir are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when coadministered. No dose adjustments are necessary for patients with normal renal function (see Victrelis® prescribing information). Zidovudine: Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Administration of clarithromycin and zidovudine should be separated by at least two hours [see Pharmacokinetics (12.3)]. The impact of co-administration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated.
Calcium Channel Blockers: Verapamil Amlodipine Diltiazem Nifedipine	Use With Caution	Verapamil: Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, [see Warnings and Precautions (5.4)]. Amlodipine, Diltiazem: [See Warnings and Precautions (5.4)] Nifedipine: Nifedipine is a substrate for CYP3A. Clarithromycin and other macrolides are known to inhibit CYP3A. There is potential of CYP3A-mediated interaction between nifedipine and clarithromycin. Hypotension and peripheral edema were observed when clarithromycin was taken concomitantly with nifedipine [see Warnings and Precautions (5.4)].
Ergot Alkaloids: Ergotamine Dihydroergotamine	Contraindicated	Ergotamine, Dihydroergotamine: Postmarketing reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4.6)].
Gastroprokinetic Agents: Cisapride	Contraindicated	Cisapride: [See Contraindications (4.2)]
HMG-CoA Reductase Inhibitors: Lovastatin Simvastatin Atorvastatin Pravastatin Fluvastatin	Contraindicated Use With Caution No Dose Adjustment	Lovastatin, Simvastatin, Atorvastatin, Pravastatin, Fluvastatin: [See Contraindications (4.5) and Warnings and Precautions (5.4)]
Hypoglycemic Agents: Nateglinide Pioglitazone Repaglinide Rosiglitazone Insulin	Use With Caution	Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)] Insulin: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]
Immunosuppressants: Cyclosporine Tacrolimus	Use With Caution	Cyclosporine: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine. Tacrolimus: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with tacrolimus.
Phosphodiesterase inhibitors: Sildenafil Tadalafil Vardenafil	Use With Caution	Sildenafil, Tadalafil, Vardenafil: Each of these phosphodiesterase inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant administration of clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil, or vardenafil will result in increased exposure of these phosphodiesterase inhibitors. Co-administration of these phosphodiesterase inhibitors with clarithromycin is not recommended. Increased systemic exposure of these drugs may occur with clarithromycin; reduction of dosage for phosphodiesterase inhibitors should be considered (see their respective prescribing information).
Proton Pump Inhibitors: Omeprazole	No Dose Adjustment	Omeprazole: The mean 24 hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when coadministered with clarithromycin as a result of increased omeprazole exposures [see Pharmacokinetics (12.3)] (see also Omeprazole under “Drugs That Affect Clarithromycin” in the table below).
Xanthine Derivatives: Theophylline	Use With Caution	Theophylline: Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations [see Pharmacokinetics (12.3)]. Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range.
Triazolobenzodiazepines and Other Related Benzodiazepines: Midazolam Alprazolam Triazolam Temazepam Nitrazepam Lorazepam	Use With Caution No Dose Adjustment	Midazolam: When oral midazolam is coadministered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated [see Warnings and Precautions (5.4) and Pharmacokinetics (12.3)]. Triazolam, Alprazolam: Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is co-administered with clarithromycin. There have been postmarketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested. In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines. Temazepam, Nitrazepam, Lorazepam: For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.
Cytochrome P450 Inducers: Rifabutin	Use With Caution	Rifabutin: Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis (see Rifabutin under “Drugs That Affect Clarithromycin” in the table below).
Other Drugs Metabolized by CYP3A: Alfentanil Bromocriptine Cilostazol Methylprednisole Vinblastine Phenobarbital St. John’s Wort	Use With Caution	There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort.
Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A: Hexobarbital Phenytoin Valproate	Use With Caution	There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.
Drugs that Affect Clarithromycin
Drug(s) that Affect the Pharmacokinetics of Clarithromycin	Recommendation	Comments
Antifungals: Itraconazole	Use With Caution	Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions (see also Itraconazole under “Drugs That Are Affected By Clarithromycin” in the table above).
Antivirals: Atazanavir Ritonavir (in patients with decreased renal function) Saquinavir (in patients with decreased renal function) Etravirine Saquinavir (in patients with normal renal function) Ritonavir (in patients with normal renal function)	Use With Caution No Dose Adjustment	Atazanavir: When clarithromycin is co-administered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology (12.3)]. Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is coadministered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors. Ritonavir: Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with ritonavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium [see Pharmacokinetics (12.3)]. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors. Saquinavir: When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (refer to ritonavir above) [see Pharmacokinetics (12.3)]. Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.
Proton Pump Inhibitors: Omeprazole	Use With Caution	Omeprazole: Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole [see Pharmacokinetics (12.3)].
Miscellaneous Cytochrome P450 Inducers: Efavirenz Nevirapine Rifampicin Rifabutin Rifapentine	Use With Caution	Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are Affected By Clarithromycin” in the table above).

Table name:

Factors	Dosage Adjustment of ABILIFY
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors	Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double usual dose over 1 to 2 weeks

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄ . Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³ I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

Table name:

Interacting Drug	Interaction
Drugs known to prolong QT interval (e.g., Class IA and Class III anti-arrhythmic agents).	Quinine Sulfate Capsules prolong QT interval, ECG abnormalities including QT prolongation and Torsades de Pointes. Avoid concomitant use (5.3).
Other antimalarials (e.g., halofantrine, mefloquine).	ECG abnormalities including QT prolongation. Avoid concomitant use (5.3, 7.2).
CYP3A4 inducers or inhibitors	Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine (7.1).
CYP3A4 and CYP2D6 substrates	Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the co-administered drug (7.2).
Digoxin	Increased digoxin plasma concentration (5.8, 7.1).

Table name:

Table 2: Drug-Thyroidal Axis Interactions
	Drug or Drug Class		Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
		Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
		Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
		Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
		Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
		Amiodarone Iodide (including iodine- containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
	Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
	Drugs that may increase		Drugs that may decrease
	serum TBG concentration		serum TBG concentration
	Clofibrate		Androgens / Anabolic Steroids
	Estrogen-containing oral		Asparaginase
	contraceptives		Glucocorticoids
	Estrogens (oral)		Slow-Release Nicotinic Acid
	Heroin / Methadone
	5-Fluorouracil
	Mitotane
	Tamoxifen
	Drugs that may cause protein-binding site displacement
	Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)		Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
	Carbamazepine Hydantoins Phenobarbital Rifampin		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
	Drugs that may decrease T ₄ 5' - deiodinase activity
	Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)		Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, Ieading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
	Miscellaneous
	Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives		Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
	Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
	Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin		Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
	Cardiac Glycosides		Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
	Cytokines - Interferon-α - Interleukin-2		Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
	Growth Hormones - Somatrem - Somatropin		Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
	Ketamine		Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
	Methylxanthine Bronchodilators - (e.g., Theophylline)		Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
	Radiographic Agents		Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
	Sympathomimetics		Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
	Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics		These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name:

Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitors (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of this product. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. ( 2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents	Carefully monitor blood glucose ( 5.12, 7.3)

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

Table name:

Factors	Dosage Adjustments for Aripiprazole Tablets
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors	Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double usual dose over 1 to 2 weeks

Table name:

Oral hypoglycemics
Coumarin-type
anticoagulants
Phenytoin
Cyclosporine
Rifampin
Theophylline
Voriconazole
Tofacitinib
Oral Contraceptives
Hydrochlorothiazide
Amitriptyline, nortriptyline
Azithromycin
Calcium Channel Blockers
Cyclophosphamide

Quinidine
Halofantrine
Losartan
Non-steroidal
anti-inflammatory drugs
Saquinavir
Vinca Alkaloids
Zidovudine
Terfenadine
Cisapride
Astemizole
Rifabutin
Tacrolimus
Short-acting
benzodiazepines

Triazolam
Pimozide
Alfentanil
Amphotericin B
Carbamazepine
Celecoxib
Fentanyl
HMG-CoA reductase
inhibitors
Methadone
Prednisone
Sirolimus
Vitamin A

Table name:

NA - Not available/reported
Digoxin concentrations increased > 50%
	Digoxin Serum Concentration Increase	Digoxin AUC Increase	Recommendations
Amiodarone	70%	NA	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin dose by approximately 30% to 50% and continue monitoring.
Captopril	58%	39%
Nitrendipine	57%	15%
Propafenone	35-85%	NA
Quinidine	100%	NA
Ranolazine	87%	88%
Ritonavir	NA	86%
Verapamil	50-75%	NA
Digoxin concentrations increased < 50%
Carvedilol	16%	14%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin dose by approximately 15% to 30% and continue monitoring.
Diltiazem	20%	NA
Nifedipine	45%	NA
Rabeprazole	29%	19%
Telmisartan	20%	NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, Azithromycin, Clarithromycin, Cyclosporine, Diclofenac, Diphenoxylate, Epoprostenol, Erythromycin, Esomeprazole, Indomethacin, Itraconazole, Ketoconazole, Lansoprazole, Metformin, Omeprazole, Propantheline, Spironolactone, Tetracycline			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, Activated Charcoal, Albuterol, Antacids, Anticancer drugs, Cholestyramine, Colestipol, Exenatide, Kaolin-pectin, Meals High in Bran, Metoclpramide, Miglitol, Neomycin, Rifampin, Salbutamol, St.John's Wort, Sucralfate, Sulfasalazine			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20% to 40% as necessary.
No significant Digoxin concentration changes
Please refer to section 12.3 for a complete list of drugs which were studied but reported no significant changes on digoxin exposure.			No additional actions are required.

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Bleeding Times
Clinical Impact:	Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention:	This effect should be kept in mind when bleeding times are determined.
Porter-Silber Test
Clinical Impact:	The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention:	Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary Assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact:	Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention:	This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.

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Table 6. Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interactions [see Dosage and Administration (2)]
Concomitant Drug Class: Drug Name	Effect on Concentration of Dolutegravir and/or Concomitant Drug	Clinical Comment
HIV-1 Antiviral Agents
Non-nucleoside reverse transcriptase inhibitor: Etravirine^a	↓Dolutegravir	Use of TIVICAY with etravirine without coadministration of atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir is not recommended.
Non-nucleoside reverse transcriptase inhibitor: Efavirenz^a	↓Dolutegravir	Adjust dose of TIVICAY to 50 mg twice daily for treatment-naïve and treatment-experienced, INSTI-naïve adult patients. In pediatric patients, increase the weight-based dose to twice daily (Table 2). Use alternative combinations that do not include metabolic inducers where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance.^b
Non-nucleoside reverse transcriptase inhibitor: Nevirapine	↓Dolutegravir	Avoid coadministration with nevirapine because there are insufficient data to make dosing recommendations.
Protease inhibitor: Fosamprenavir/ritonavir^a Tipranavir/ritonavir^a	↓Dolutegravir	Adjust dose of TIVICAY to 50 mg twice daily for treatment-naïve and treatment-experienced, INSTI-naïve adult patients. In pediatric patients, increase the weight-based dose to twice daily (Table 2). Use alternative combinations that do not include metabolic inducers where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance.^b
Other Agents
Carbamazepine^a	↓Dolutegravir	Adjust dose of TIVICAY to 50 mg twice daily in treatment-naïve or treatment-experienced, INSTI-naïve adult patients. In pediatric patients, increase the weight-based dose to twice daily (Table 2). Use alternative treatment that does not include carbamazepine where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance.^b
Oxcarbazepine Phenytoin Phenobarbital St. John’s wort (Hypericum perforatum)	↓Dolutegravir	Avoid coadministration with TIVICAY because there are insufficient data to make dosing recommendations.
Medications containing polyvalent cations (e.g., Mg or Al): Cation-containing antacids^a or laxatives Sucralfate Buffered medications	↓Dolutegravir	Administer TIVICAY 2 hours before or 6 hours after taking medications containing polyvalent cations.
Oral calcium or iron supplements, including multivitamins containing calcium or iron ^a	↓Dolutegravir	Administer TIVICAY 2 hours before or 6 hours after taking supplements containing calcium or iron. Alternatively, TIVICAY and supplements containing calcium or iron can be taken together with food.
Metformin	↑Metformin	With concomitant use, limit the total daily dose of metformin to 1,000 mg either when starting metformin or TIVICAY. When stopping TIVICAY, the metformin dose may require an adjustment. Monitoring of blood glucose when initiating concomitant use and after withdrawal of TIVICAY is recommended.
Rifampin^a	↓Dolutegravir	Adjust dose of TIVICAY to 50 mg twice daily for treatment-naïve and treatment-experienced, INSTI-naïve adult patients. In pediatric patients, increase the weight-based dose to twice daily (Table 2). Use alternatives to rifampin where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance.^b

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Bleeding times
Clinical Impact:	Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention:	This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact:	The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention:	Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact:	Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention:	This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including: antacids, sucralfate, multivitamins	Decreased moxifloxacin hydrochloride absorption. Take moxifloxacin hydrochloride tablets at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time/INR, and bleeding. (6, 7.2, 12.3)
Class IA and Class III antiarrhythmics:	Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.3, 7.4)
Antidiabetic agents	Carefully monitor blood glucose. ( 5.10, 7.3)

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Table 4 Established and Other Potentially SignificantThis table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
Concomitant Drug Class: Drug Name	Effect	Clinical Comment
Antiretroviral agents
Protease inhibitor: atazanavir	↓atazanavir concentration ↑ tenofovir concentration	Coadministration of atazanavir with ATRIPLA is not recommended. Coadministration of atazanavir with either efavirenz or tenofovir DF decreases plasma concentrations of atazanavir. The combined effect of efavirenz plus tenofovir DF on atazanavir plasma concentrations is not known. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA.
Protease inhibitor: fosamprenavir calcium	↓ amprenavir concentration	Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and ATRIPLA with respect to safety and efficacy have not been established. Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when ATRIPLA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when ATRIPLA is administered with fosamprenavir plus ritonavir twice daily.
Protease inhibitor: indinavir	↓ indinavir concentration	The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz.
Protease inhibitor: lopinavir/ritonavir	↓ lopinavir concentration ↑ tenofovir concentration	A dose increase of lopinavir/ritonavir to 600/150 mg (3 tablets) twice daily may be considered when used in combination with efavirenz in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). Patients should be monitored for tenofovir-associated adverse reactions. ATRIPLA should be discontinued in patients who develop tenofovir-associated adverse reactions.
Protease inhibitor: ritonavir	↑ ritonavir concentration ↑ efavirenz concentration	When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when ATRIPLA is used in combination with ritonavir.
Protease inhibitor: saquinavir	↓ saquinavir concentration	Should not be used as sole protease inhibitor in combination with ATRIPLA.
CCR5 co-receptor antagonist: maraviroc	↓ maraviroc concentration	Efavirenz decreases plasma concentrations of maraviroc. Refer to the full prescribing information for maraviroc for guidance on coadministration with ATRIPLA.
NRTI: didanosine	↑ didanosine concentration	Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis and neuropathy. In patients weighing >60 kg, the didanosine dose should be reduced to 250 mg if coadministered with ATRIPLA. Data are not available to recommend a dose adjustment of didanosine for patients weighing <60 kg. Coadministration of ATRIPLA and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions. For additional information, please consult the Videx / Videx EC (didanosine) prescribing information.
Other agents
Anticoagulant: warfarin	↑ or ↓ warfarin concentration	Plasma concentrations and effects potentially increased or decreased by efavirenz.
Anticonvulsants: carbamazepine	↓ carbamazepine concentration ↓ efavirenz concentration	There are insufficient data to make a dose recommendation for ATRIPLA. Alternative anticonvulsant treatment should be used.
phenytoin phenobarbital	↓ anticonvulsant concentration ↓ efavirenz concentration	Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
Antidepressants: bupropion	↓ buproprion concentration	The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded.
sertraline	↓ sertraline concentration	Increases in sertraline dose should be guided by clinical response.
Antifungals: itraconazole	↓ itraconazole concentration ↓ hydroxy-itraconazole concentration	Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
ketoconazole	↓ ketoconazole concentration	Drug interaction trials with ATRIPLA and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole.
posaconazole	↓ posaconazole concentration	Avoid concomitant use unless the benefit outweighs the risks.
Anti-infective: clarithromycin	↓ clarithromycin concentration ↑ 14-OH metabolite concentration	Clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of ATRIPLA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with ATRIPLA.
Antimycobacterial: rifabutin	↓ rifabutin concentration	Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
Antimycobacterial: rifampin	↓ efavirenz concentration	If ATRIPLA is coadministered with rifampin to patients weighing 50 kg or more, an additional 200 mg/day of efavirenz is recommended.
Calcium channel blockers: diltiazem	↓ diltiazem concentration ↓ desacetyl diltiazem concentration ↓ N-monodes-methyl diltiazem concentration	Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of ATRIPLA is necessary when administered with diltiazem.
Others (e.g., felodipine, nicardipine, nifedipine, verapamil)	↓ calcium channel blocker	No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker).
HMG-CoA reductase inhibitors: atorvastatin pravastatin simvastatin	↓ atorvastatin concentration ↓ pravastatin concentration ↓ simvastatin concentration	Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with efavirenz. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
Hormonal contraceptives:
Oral: ethinyl estradiol/norgestimate	↓ active metabolites of norgestimate	A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed.
Implant: etonogestrel	↓ etonogestrel	A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.
Immunosuppressants: cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A	↓ immuno-suppressant	Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by efavirenz. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with ATRIPLA.
Narcotic analgesic: methadone	↓ methadone concentration	Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T ₄ and T ₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT ₄. Continued administration results in a decrease in serum T ₄ and normal FT ₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T ₄ and T ₃ to TBG and transthyretin. An initial increase in serum FT ₄, is followed by return of FT ₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T ₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T ₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T ₄ to T ₃, leading to decreased T ₃ levels. However, serum T ₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T ₃ and T ₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T ₃ concentrations by 30% with minimal change in serum T ₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T ₃ and T ₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name:

Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name:

Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C_max and AUC_τ)	Recommendations for Drug Dosage Adjustment/Comments
Sirolimus* (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin* (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (400 mg q24h) (CYP3A4 Inhibition) Efavirenz (300 mg q24h) (CYP3A4 Inhibition)	Significantly Increased Slight Increase in AUC_τ	Contraindicated When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h) (CYP3A4 Inhibition) Low-dose Ritonavir (100 mg q12h)	No Significant Effect of Voriconazole on Ritonavir C_max or AUC_τ Slight Decrease in Ritonavir C_max and AUC_τ	Contraindicated because of significant reduction of voriconazole C_max and AUC_τ Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole C_max and AUC_τ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated
Cyclosporine* (CYP3A4 Inhibition)	AUC_τ Significantly Increased; No Significant Effect on C_max	When initiating therapy with voriconazole in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary
Methadone*** (CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7)].
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see Drug Interactions (7)].
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7)].
NSAIDs**** including ibuprofen and diclofenac (CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [see Drug Interactions (7)].
Tacrolimus* (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with voriconazole in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin* (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)**	Increased	Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin* (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole* (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with voriconazole in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects on Indinavir Exposure In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	No dosage adjustment for indinavir when coadministered with voriconazole Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIs***** (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Reserve azole antifungals, including voriconazole, for patients receiving a vinca alkaloid who have no alternative antifungal treatment options.
Everolimus (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Concomitant administration of voriconazole and everolimus is not recommended.

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Table 2. Drugs That May Decrease T4 Absorption (Hypothyroidism)
Potential impact: Concurrent use may reduce the efficacy of SYNTHROID by binding and delaying or preventing absorption, potentially resulting in hypothyroidism.
Drug or Drug Class	Effect
Calcium Carbonate Ferrous Sulfate	Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer SYNTHROID at least 4 hours apart from these agents.
Orlistat	Monitor patients treated concomitantly with orlistat and SYNTHROID for changes in thyroid function.
Bile Acid Sequestrants - Colesevelam - Cholestyramine - Colestipol Ion Exchange Resins - Kayexalate - Sevelamer	Bile acid sequestrants and ion exchange resins are known to decrease levothyroxine absorption. Administer SYNTHROID at least 4 hours prior to these drugs or monitor TSH levels.
Other drugs: Proton Pump Inhibitors Sucralfate Antacids - Aluminum & Magnesium Hydroxides - Simethicone	Gastric acidity is an essential requirement for adequate absorption of levothyroxine. Sucralfate, antacids and proton pump inhibitors may cause hypochlorhydria, affect intragastric pH, and reduce levothyroxine absorption. Monitor patients appropriately.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T ₄ and T ₃levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT ₄ . Continued administration results in a decrease in serum T ₄ and normal FT ₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T ₄ and T ₃ to TBG and transthyretin. An initial increase in serum FT ₄ is followed by return of FT ₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T ₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T ₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T ₄ to T ₃, leading to decreased T ₃ levels. However, serum T ₄levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T ₃ and T ₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T ₃concentrations by 30% with minimal change in serum T ₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T ₃ and T ₄levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³ I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Table 4 Established and Other Potentially SignificantThis table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
Concomitant Drug Class: Drug Name	Effect	Clinical Comment
HIV antiviral agents
Protease inhibitor: atazanavir	↓atazanavir ↑ tenofovir	Coadministration of atazanavir with ATRIPLA is not recommended. Coadministration of atazanavir with either efavirenz or tenofovir DF decreases plasma concentrations of atazanavir. The combined effect of efavirenz plus tenofovir DF on atazanavir plasma concentrations is not known. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA.
Protease inhibitor: fosamprenavir calcium	↓ amprenavir	Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and ATRIPLA with respect to safety and efficacy have not been established. Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when ATRIPLA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when ATRIPLA is administered with fosamprenavir plus ritonavir twice daily.
Protease inhibitor: indinavir	↓ indinavir	The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz.
Protease inhibitor: lopinavir/ritonavir	↓ lopinavir ↑ tenofovir	Do not use once daily administration of lopinavir/ritonavir. Dose adjustment of lopinavir/ritonavir is recommended when coadministered with efavirenz. Refer to the full prescribing information for lopinavir/ritonavir for guidance on coadministration with efavirenz- or tenofovir-containing regimens, such as ATRIPLA. Patients should be monitored for tenofovir-associated adverse reactions.
Protease inhibitor: ritonavir	↑ ritonavir ↑ efavirenz	When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when ATRIPLA is used in combination with ritonavir.
Protease inhibitor: saquinavir	↓ saquinavir	Appropriate doses of the combination of efavirenz and saquinavir/ritonavir with respect to safety and efficacy have not been established.
CCR5 co-receptor antagonist: maraviroc	↓ maraviroc	Efavirenz decreases plasma concentrations of maraviroc. Refer to the full prescribing information for maraviroc for guidance on coadministration with ATRIPLA.
NRTI: didanosine	↑ didanosine	Coadministration of ATRIPLA and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions including pancreatitis, lactic acidosis, and neuropathy. A dose reduction of didanosine is recommended when co-administered with tenofovir DF. For additional information on coadministration with tenofovir DF-containing products, please refer to the didanosine prescribing information.
NNRTI: Other NNRTIs	↑ or ↓ efavirenz and/or NNRTI	Combining two NNRTIs has not been shown to be beneficial. ATRIPLA contains efavirenz and should not be coadministered with other NNRTIs.
Integrase strand transfer inhibitor: raltegravir	↓ raltegravir	Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
Hepatitis C antiviral agents
Protease inhibitor: boceprevir	↓ boceprevir	Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with efavirenz, which may result in loss of therapeutic effect. The combination should be avoided.
Protease inhibitor: telaprevir	↓ telaprevir ↓ efavirenz	Concomitant administration of telaprevir and efavirenz resulted in reduced steady-state exposures to telaprevir and efavirenz.
Other agents
Anticoagulant: warfarin	↑ or ↓ warfarin	Plasma concentrations and effects potentially increased or decreased by efavirenz.
Anticonvulsants: carbamazepine	↓ carbamazepine ↓ efavirenz	There are insufficient data to make a dose recommendation for ATRIPLA. Alternative anticonvulsant treatment should be used.
phenytoin phenobarbital	↓ anticonvulsant ↓ efavirenz	Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
Antidepressants: bupropion	↓ buproprion	The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded.
sertraline	↓ sertraline	Increases in sertraline dose should be guided by clinical response.
Antifungals: itraconazole	↓ itraconazole ↓ hydroxy-itraconazole	Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
ketoconazole	↓ ketoconazole	Drug interaction trials with ATRIPLA and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole.
posaconazole	↓ posaconazole	Avoid concomitant use unless the benefit outweighs the risks.
Anti-infective: clarithromycin	↓ clarithromycin ↑ 14-OH metabolite	Clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of ATRIPLA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with ATRIPLA.
Antimycobacterial: rifabutin	↓ rifabutin concentration	Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
rifampin	↓ efavirenz	If ATRIPLA is coadministered with rifampin to patients weighing 50 kg or more, an additional 200 mg/day of efavirenz is recommended.
Calcium channel blockers: diltiazem	↓ diltiazem ↓ desacetyl diltiazem ↓ N-monodes-methyl diltiazem	Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of ATRIPLA is necessary when administered with diltiazem.
Others (e.g., felodipine, nicardipine, nifedipine, verapamil)	↓ calcium channel blocker	No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker).
HMG-CoA reductase inhibitors: atorvastatin pravastatin simvastatin	↓ atorvastatin ↓ pravastatin ↓ simvastatin	Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with efavirenz. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
Hormonal contraceptives:
Oral: ethinyl estradiol/norgestimate	↓ active metabolites of norgestimate	A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed.
Implant: etonogestrel	↓ etonogestrel	A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.
Immunosuppressants: cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A	↓ immuno-suppressant	Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by efavirenz. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with ATRIPLA.
Narcotic analgesic: methadone	↓ methadone	Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.

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Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.6).]
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported . Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [see Adverse Reactions (6.1).]
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution 2-fold increase in exposure	Monitor for sildenafil toxicity (see Pharmacokinetics -(12.3)-] .
Duloxetine	Avoid Use 5-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx ^® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2)].	Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Table 6 Clinically Important Drug Interactions
Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Tricyclic antidepressants	Increase blood pressure and may counteract clonidine’s hypotensive effects	Monitor blood pressure and adjust as needed
Antihypertensive drugs	Potentiate clonidine’s hypotensive effects	Monitor blood pressure and adjust as needed
CNS depressants	Potentiate sedating effects	Avoid use
Drugs that affect sinus node function or AV node conduction (e.g., digitalis, calcium channel blockers, beta blockers)	Potentiate bradycardia and risk of AV block	Avoid use

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Table 4: Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
Drug Name	Effect on Concentration of Nevirapine or Concomitant Drug	Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/RitonavirThe interaction between immediate-release nevirapine and the drug was evaluated in a clinical study. The results of drug interaction studies with immediate-release nevirapine are expected to also apply to nevirapine extended-release tablets.	↓ Atazanavir ↑ Nevirapine	Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir	↓ Amprenavir ↑ Nevirapine	Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir	↓ Amprenavir ↑ Nevirapine	No dosing adjustments are required when nevirapine is co-administered with 700 mg/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir	↓ Indinavir	The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir	↓ Lopinavir	Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500 mg/125 mg tablets twice daily or 533 mg/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra^® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir	↓ Nelfinavir M8 Metabolite ↓ Nelfinavir C_min	The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/Ritonavir	The interaction between nevirapine and saquinavir/ritonavir has not been evaluated	The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz	↓ Efavirenz	The appropriate doses of these combinations with respect to safety and efficacy have not been established.
Delavirdine Etravirine Rilpivirine		Plasma concentrations may be altered. Nevirapine should not be co-administered with another NNRTI as this combination has not been shown to be beneficial.
Hepatitis C Antiviral Agents
Boceprevir	Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine.	Nevirapine and boceprevir should not be co-administered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy.
Telaprevir	Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir.	Nevirapine and telaprevir should not be co-administered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events.
Other Agents
Analgesics: Methadone	↓ Methadone	Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics: Amiodarone, disopyramide, lidocaine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Antibiotics: Clarithromycin	↓ Clarithromycin ↑ 14-OH clarithromycin	Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Rifabutin	↑ Rifabutin	Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin	↓ Nevirapine	Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants: Carbamazepine, clonazepam, ethosuximide	Plasma concentrations of nevirapine and the anticonvulsant may be decreased.	Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals: Fluconazole	↑ Nevirapine	Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Ketoconazole	↓ Ketoconazole	Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Itraconazole	↓ Itraconazole	Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics: Warfarin	Plasma concentrations may be increased.	Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers: Diltiazem, nifedipine, verapamil	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Cancer chemotherapy: Cyclophosphamide	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Ergot alkaloids: Ergotamine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Motility agents: Cisapride	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Opiate agonists: Fentanyl	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Oral contraceptives: Ethinyl estradiol and Norethindrone	↓ Ethinyl estradiol ↓ Norethindrone	Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.

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Table 2: Clinically Relevant Interactions Affecting Drugs Co-Administered with Rabeprazole Sodium Delayed-Release Tablets
Antiretrovirals
Clinical Impact:	The effect of PPI on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. • Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and nelfinavir) when used concomitantly with rabeprazole may reduce antiviral effect and promote the development of drug resistance. • Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with rabeprazole may increase toxicity. • There are other antiretroviral drugs which do not result in clinically relevant interactions with rabeprazole.
	Rilpivirine-containing products: Concomitant use with rabeprazole sodium delayed-release tablets are contraindicated [see CONTRAINDICATIONS (4)]. See prescribing information.
	Atazanavir: See prescribing information for atazanavir for dosing information.
Intervention:	Nelfinavir: Avoid concomitant use with rabeprazole sodium delayed-release tablets. See prescribing information for nelfinavir.
	Saquinavir: See the prescribing information for saquinavir and monitor for potential saquinavir toxicities.
	Other antiretrovirals: See prescribing information.
Warfarin
Clinical Impact:	Increased INR and prothrombin time in patients receiving PPIs, including rabeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death [see WARNINGS AND PRECAUTIONS (5.2)].
Intervention:	Monitor INR and prothrombin time. Dose adjustment of warfarin may be needed to maintain target INR range. See prescribing information for warfarin.
Methotrexate
Clinical Impact:	Concomitant use of rabeprazole with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of methotrexate with PPIs have been conducted [see WARNINGS AND PRECAUTIONS (5.9)].
Intervention:	A temporary withdrawal of rabeprazole sodium delayed-release tablets may be considered in some patients receiving high dose methotrexate administration.
Digoxin
Clinical Impact:	Potential for increased exposure of digoxin [see CLINICAL PHARMACOLOGY (12.3)].
Intervention:	Monitor digoxin concentrations. Dose adjustment of digoxin may be needed to maintain therapeutic drug concentrations. See prescribing information for digoxin.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole, itraconazole)
Clinical Impact:	Rabeprazole can reduce the absorption of drugs due to its effect on reducing intragastric acidity.
Intervention:	Mycophenolate mofetil (MMF): Co-administration of PPIs in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving PPIs and MMF. Use rabeprazole sodium delayed-release tablets with caution in transplant patients receiving MMF. See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:	Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:	See CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS in prescribing information for clarithromycin. See DRUG INTERACTIONS in prescribing information for amoxicillin.

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^a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
^b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)	VIAGRA 25 mg
Supine	7.4 (-0.9, 15.7)
Standing	6.0 (-0.8, 12.8)

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Table 1: Clinically Significant Drug Interactions with DILAUDID
Benzodiazepines and other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.5)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue DILAUDID Oral Solution or DILAUDID Tablets if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.3)]. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Intervention:	The use of DILAUDID Oral Solution or DILAUDID Tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of DILAUDID Oral Solution or DILAUDID Tablets and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine,
Muscle Relaxants
Clinical Impact:	Hydromorphone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of DILAUDID Oral Solution or DILAUDID Tablets and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when DILAUDID Oral Solution or DILAUDID Tablets is used concomitantly with anticholinergic drugs.

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Figure 2: Effect of venlafaxine on the pharmacokinetics interacting drugs and their active metabolites.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. ( 2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidibetic agents	Carefully monitor blood glucose ( 5.11, 7.3)

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
*Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol, systemic and inhaled	felodipinefinasteride	nizatidinenorfloxacin
amoxicillin	hydrocortisone	ofloxacin
ampicillin, with or without sulbactam	isoflurane isoniazid	omeprazole prednisone, prednisolone
atenolol	isradipine	ranitidine
azithromycin	influenza vaccine	rifabutin
caffeine, dietary ingestion	ketoconazo lelomefloxacin	roxithromycin sorbitol
cefaclor	mebendazole	(purgative doses do not
co-trimoxazole (trimethoprim and sulfamethoxazole)	medroxyprogesteronemethylprednisolone	inhibit theophylline absorption)
diltiazem	metronidazole	sucralfate
dirithromycin	metoprolol	terbutaline, systemic
enflurane	nadolol	terfenadine
famotidine	nifedipine	tetracycline
		tocainide

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Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia Coadministered Drug Dosing Schedule Effect on Active
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference)		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	Cmax	Risperidone Dose Recommendation
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed

Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine ? CBZ epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40% May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Concomitant Drug Class: Drug Name	Effect on Concentration	Clinical Comment
HIV-1 Antiviral Agents
Non-nucleoside reverse transcriptase inhibitor: Etravirine^a	↓Dolutegravir	Use of TRIUMEQ with etravirine without coadministration of atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir is not recommended.
Non-nucleoside reverse transcriptase inhibitor: Efavirenz^a	↓Dolutegravir	Adjust dolutegravir dose to 50 mg twice daily. An additional 50-mg dose of dolutegravir should be taken, separated by 12 hours from TRIUMEQ.
Non-nucleoside reverse transcriptase inhibitor: Nevirapine	↓Dolutegravir	Avoid coadministration with TRIUMEQ because there are insufficient data to make dosing recommendations.
Protease inhibitor: Fosamprenavir/ritonavir^a Tipranavir/ritonavir^a	↓Dolutegravir	Adjust dolutegravir dose to 50 mg twice daily. An additional dolutegravir 50-mg dose should be taken, separated by 12 hours from TRIUMEQ.
Other Agents
Carbamazepine^a	↓Dolutegravir	Adjust dolutegravir dose to 50 mg twice daily. An additional dolutegravir 50-mg dose should be taken, separated by 12 hours from TRIUMEQ.
Oxcarbazepine Phenytoin Phenobarbital St. John’s wort (Hypericum perforatum)	↓Dolutegravir	Avoid coadministration with TRIUMEQ because there are insufficient data to make dosing recommendations.
Medications containing polyvalent cations (e.g., Mg or Al): Cation-containing antacids^a or laxatives Sucralfate Buffered medications	↓Dolutegravir	Administer TRIUMEQ 2 hours before or 6 hours after taking medications containing polyvalent cations.
Oral calcium and iron supplements, including multivitamins containing calcium or iron^a	↓Dolutegravir	Administer TRIUMEQ 2 hours before or 6 hours after taking supplements containing calcium or iron. Alternatively, TRIUMEQ and supplements containing calcium or iron can be taken together with food.
Metformin^a	↑Metformin	With concomitant use, limit the total daily dose of metformin to 1,000 mg either when starting metformin or TRIUMEQ. When stopping TRIUMEQ, the metformin dose may require an adjustment. Monitoring of blood glucose when initiating concomitant use and after withdrawal of TRIUMEQ is recommended.
Rifampin^a	↓Dolutegravir	Adjust dolutegravir dose to 50 mg twice daily. An additional 50-mg dose of dolutegravir should be taken, separated by 12 hours from TRIUMEQ.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 7.6, 7.8, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 Inhibitors, (e.g., itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with VYTORIN
Verapamil, diltiazem	Do not exceed 10/10 mg VYTORIN daily
Amiodarone, amlodipine, ranolazine	Do not exceed 10/20 mg VYTORIN daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Classes of Drugs
Adrenal Cortical Steroid Inhibitors Antacids Antianxiety Agents Antiarrhythmics† Antibiotics† Anticonvulsants† Antidepressants† Antihistamines Antineoplastics†	Antipsychotic Medications Antithyroid Drugs† Barbiturates Diuretics† Enteral Nutritional Supplements Fungal Medications, Systemic† Gastric Acidity and Peptic Ulcer Agents† Hypnotics†	Hypolipidemics† Bile Acid-Binding Resins† HMG-CoA Reductase Inhibitors† Immunosuppressives Oral Contraceptives, Estrogen Containing Selective Estrogen Receptor Modulators Steroids, Adrenocortical† Tuberculosis Agents† Vitamins†

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine	Do not exceed 10 mg atorvastatin daily
Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir)	Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used.

Table name: ContraindicatedAvoid UseUse with cautionUse with cautionUse with caution

Table 8: Drugs That are Affected by and Affecting CIPRO IV
Drugs That are Affected by CIPRO IV
Drug(s)	Recommendation	Comments
Tizanidine
Concomitant administration of tizanidine and CIPRO IV is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)]
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of CIPRO IV with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [eee Warnings and Precautions (5.9)].
Drugs Known to Prolong QT Interval
CIPRO IV may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.11) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when CIPRO IV and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs [see Adverse Reactions (6.1)].
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon CIPRO IV discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of CIPRO IV with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of CIPRO IV to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of CIPRO IV with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant CIPRO IV therapy is indicated.
Ropinirole
Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with CIPRO IV [see Warnings and Precautions (5.15)].
Clozapine
Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with CIPRO IV are advised.
NSAIDs
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution Two-fold increase in exposure	Monitor for sildenafil toxicity [see Clinical Pharmacology (12.3)].
Duloxetine	Avoid Use Five-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	CIPRO IV inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of CIPRO
Probenecid	Use with caution (interferes with renal tubular secretion of CIPRO and increases CIPRO serum levels)	Potentiation of CIPRO IV toxicity may occur.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.12, 7.3)

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TABLE 2. Mean (± S.D.) Pharmacokinetic Parameters for Estradiol, Estrone, and Equilin Following Coadministration of Conjugated Estrogens 0.625 mg and Progesterone Capsules 200 mg for 12 Days to Postmenopausal Women
^a Total estrogens is the sum of conjugated and unconjugated estrogen.
	Conjugated Estrogens			Conjugated Estrogens plus Progesterone Capsules
Drug	C_max (ng/mL)	T_max (hr)	AUC_(0-24h) (ng × h/mL)	C_max (ng/mL)	T_max (hr)	AUC_(0-24h) (ng × h/mL)
Estradiol	0.037 ± 0.048	12.7 ± 9.1	0.676 ± 0.737	0.030 ± 0.032	17.32 ± 1.21	0.561 ± 0.572
Estrone Total^a	3.68 ± 1.55	10.6 ± 6.8	61.3 ± 26.36	4.93 ± 2.07	7.5 ± 3.8	85.9 ± 41.2
Equilin Total^a	2.27 ± 0.95	6.0 ± 4.0	28.8 ± 13.0	3.22 ± 1.13	5.3 ± 2.6	38.1 ± 20.2

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Interacting Drug	Interaction
Drugs known to prolong QT interval (e.g., Class IA and Class III antiarrhythmic agents).	QUALAQUIN prolongs QT interval, ECG abnormalities including QT prolongation and Torsades de Pointes. Avoid concomitant use (5.3).
Other antimalarials (e.g., halofantrine, mefloquine).	ECG abnormalities including QT prolongation. Avoid concomitant use (5.3, 7.2).
CYP3A4 inducers or inhibitors	Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine (7.1).
CYP3A4 and CYP2D6 substrates	Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the co-administered drug (7.2).
Digoxin	Increased digoxin plasma concentration (5.8, 7.1).

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Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.7)].
Benzodiazepines (e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.7)]	Monitor sedation and blood pressure. Adjust dose accordingly.

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Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of aripiprazole with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.8)].
Benzodiazepines (e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.8)].	Monitor sedation and blood pressure. Adjust dose accordingly.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir )	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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CYP2C19 or CYP3A4 Inducers
Clinical Impact:	Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3) ].
Intervention:	S t . John’s Wort, rifampin: Avoid concomitant use with Omeprazole Delayed-Release Capsules [ see W arnings and P recautions (5.9)] . Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:	Increased exposure of omeprazole [see C l i n i cal Pharmacology (12.3)].
Intervention:	V oriconazole: Dose adjustment of Omeprazole Delayed-Release Capsules is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole.

Table name:

albuterol, systemic and inhaled	mebendazole
amoxicillin	medroxyprogesterone
ampicillin, with or without	methylprednisolone
sulbactam	metronidazole
atenolol	metoprolol
azithromycin	nadolol
caffeine, dietary ingestion	nifedipine
cefaclor	nizatidine
co-trimoxazole (trimethoprim and sulfamethoxazole)	norfloxacin
co-trimoxazole (trimethoprim and sulfamethoxazole)	ofloxacin
diltiazem	omeprazole
dirithromycin	prednisone, prednisolone
enflurane	ranitidine
famotidine	rifabutin
felodipine	roxithromycin
finasteride	Sorbitol (purgative doses do not inhibit
hydrocortisone	theophylline absorption)
isoflurane	sucralfate
isoniazid	terbutaline, systemic
isradipine	terfenadine
influenza vaccine	tetracycline
ketoconazole	tocainide
lomefloxacin

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Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.6).]
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported . Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [see Adverse Reactions (6.1).]
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution 2-fold increase in exposure	Monitor for sildenafil toxicity (see Pharmacokinetics -(12.3)-] .
Duloxetine	Avoid Use 5-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx ^® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2)].	Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

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Drugs That Interfere with Hemostasis
Clinical Impact:	Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of celecoxib capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11) ].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2) ]. In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200-400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100-325 mg).
Intervention:	Concomitant use of celecoxib capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11) ]. Celecoxib capsules are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of celecoxib capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of celecoxib capsules and ACE-inhibitors or ARBs in patients who are elderly, volume- depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6) ]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of celecoxib capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6) ].
Digoxin
Clinical Impact:	The concomitant use of celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of celecoxib capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of celecoxib capsules and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Celecoxib capsules have no effect on methotrexate pharmacokinetics.
Intervention:	During concomitant use of celecoxib capsules and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of celecoxib capsules and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of celecoxib capsules and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2) ].
Intervention:	The concomitant use of celecoxib with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of celecoxib capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of celecoxib capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or inducers
Clinical Impact:	Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib.
Intervention	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers [see Clinical Pharmacology (12.3) ].
CYP2D6 substrates
Clinical Impact:	In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs.
Intervention	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates [see Clinical Pharmacology (12.3) ].
Corticosteroids
Clinical Impact:	Concomitant use of corticosteroids with celecoxib capsules may increase the risk of GI ulceration or bleeding.
Intervention	Monitor patients with concomitant use of celecoxib capsules with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)].

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DRUG	DISCRIPTION OF INTERACTION
Corticosteroids	Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying agents	Increases plasma salicylate levels.
Alkcanizing agents	Decreased plasma salicylate levels.

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Drugs That Interfere with Hemostasis
Clinical Impact:	Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of indomethacin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions ( 5.11 )].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions ( 5.2 ) ].
Intervention:	Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions ( 5.11 )].Indomethacin is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of indomethacin capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.During concomitant use of indomethacin capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions ( 5.6 )].When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.It has been reported that the addition of triamterene to a maintenance schedule of Indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together.Both indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently [ see Warnings and Precautions ( 5.6 )].
Intervention:	Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels. [ see Warnings and Precautions ( 5.6 )].
Digoxin
Clinical Impact:	The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention:	During concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions ( 5.2 )]. Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin [see Clinical Pharmacology ( 12.3 )].In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage.
Intervention:	The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Probenecid
Clinical Impact:	When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased.
Intervention:	During the concomitant use of indomethacin and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments.

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Table 3. Drug(s) Affecting Pharmacokinetics of CRESEMBA
^a400 mg of lopinavir in combination with 100 mg of ritonavir.
	Recommendation	Comments
Ketoconazole	Contraindicate coadministration of all potent CYP3A4 inhibitors	There is more than a 5-fold increase in exposure of isavuconazole upon coadministration with ketoconazole [see Clinical Pharmacology (12.3)].
Lopinavir/ritonavir^a	Caution is advised when CRESEMBA is coadministered with lopinavir/ritonavir	There is a 96% increase in exposure of isavuconazole when coadministered with lopinavir/ritonavir [see Clinical Pharmacology (12.3)].
Rifampin	Contraindicate coadministration of all potent CYP3A4 inducers	There is a 97% decrease in exposure of isavuconazole upon coadministration with rifampin [see Clinical Pharmacology (12.3)].

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Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [ see Contraindications (4.2) ] .
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [ s ee Warnings and Precautions (5.9) ] .
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.11) and Use in Specific Populations (8.5) ].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were coadministered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is coadministered with oral antidiabetic drugs [ s ee Adverse Reactions (6.1) ] .
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is coadministered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after coadministration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.16) ].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after coadministration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution Two-fold increase in exposure	Monitor for sildenafil toxicity [ s ee C li n ic a l Pha r m a c o l og y ( 1 2 .3)].
Duloxetine	Avoid Use Five-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx^® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2.4) ].	Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

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Inhibitors of CYP3A4
Clinical Impact:	The concomitant use of fentanyl transdermal system and CYP3A4 inhibitors can increase the plasma concentration of fentanyl, resulting in increased or prolonged opioid effects particularly when an inhibitor is added after a stable dose of fentanyl transdermal system is achieved [see Warnings and Precautions (5.5)]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl transdermal system plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to fentanyl.
Intervention:	If concomitant use is necessary, consider dosage reduction of fentanyl transdermal system until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the fentanyl transdermal system dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir), grape fruit juice
CYP3A4 Inducers
Clinical Impact:	The concomitant use of fentanyl transdermal system and CYP3A4 inducers can decrease the plasma concentration of fentanyl [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to fentanyl [see Warnings and Precautions (5.5)]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention:	If concomitant use is necessary, consider increasing the fentanyl transdermal system dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider fentanyl transdermal system dosage reduction and monitor for signs of respiratory depression.
Examples:	Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.7)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions 5.10].
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue fentanyl transdermal system if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.10)] or opioid toxicity (e.g., respiratory depression, coma).
Intervention:	The use of fentanyl transdermal system is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of fentanyl transdermal system and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Fentanyl transdermal system may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of fentanyl transdermal system and/or the muscle relaxant as necessary.

Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl transdermal system is used concomitantly with anticholinergic drugs.

Table 3: Clinically Relevant Interactions Affecting Drugs Co-Administered with Omeprazole and Interaction with Diagnostics
Antiretrovirals
Clinical Impact:	The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
Intervention:	Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications (4)]. Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:	Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention:	Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact:	Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].
Intervention:	A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact:	Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)]. There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention:	Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6)].
Citalopram
Clinical Impact:	Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention:	Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:	Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].
Intervention:	Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:	Potential for increased exposure of phenytoin.
Intervention:	Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:	Increased exposure of diazepam [see Clinical Pharmacology (12.3)].
Intervention:	Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:	Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention:	Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:	Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:	Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)]. See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:	Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:	See Contraindications, Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact:	Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention:	Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:	Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10), Clinical Pharmacology (12.2)].
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:	Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact:	There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:	An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:	There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:	Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.

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Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio Change relative to reference)		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	Cmax	Risperidone Dose Recommendation
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Table 7 Summary of AED Interactions with Oxcarbazepine Tablets, USP
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Tablets Dose (mg/day)	Influence of Oxcarbazepine Tablets on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400-2000	900	ncnc denotes a mean change of less than 10%	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100-150	600-1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250-500	600-1800 >1200-2400	nc ^, Pediatrics up to 40% increaseMean increase in adults at high oxcarbazepine tablets, USP doses [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400-2800	600-1800	nc	18% decrease [CI: 13% decrease, 40% decrease]

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AED Co - administered	AED Concentration	Topiramate Concentration
Phenytoin	NCor25%increase ^a	48%decrease
Carbamazepine(CBZ)	NC	40%decrease
CBZepoxide ^b	NC	NE
Valproic acid	11%decrease	14%decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NCatTPM dosesupto400 mg/day	13%decrease

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C Protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Rifabutin Interaction StudiesND - No data
AUC - Area under the Concentration vs. Time Curve
Cmax - Maximum serum concentration
Coadministered Drugs	Effect on Rifabutin	Effect on Coadministered Drug	Comments
ANTIVIRALS
Amprenavir	2.9-fold ↑ AUC, 2.2-fold ↑ Cmax	No significant change in kinetics.	A 50% reduction in the rifabutin dose is recommended when combined with amprenavir. Increased monitoring for adverse reactions is warranted.
Delavirdine	ND	Oral clearance ↑ 5-fold resulting in significantly lower mean trough plasma concentrations (18±15 to 1.0±0.7 µM)	Study conducted in HIV-1 infected patients Rifabutin is not recommended for patients dosed with delavirdine mesylate 400 mg q8h.
Didanosine	No significant change in kinetics.	No significant change in kinetics at steady state.
Fosamprenavir/ritonavir	64% ↑ AUC - Drug plus active metabolite	35% ↑ AUC and 36% ↑ Cmax, no effect Ctrough (amprenavir)	Dosage reduction of rifabutin by at least 75% (to 150 mg every other day or three times per week) is recommended when combined with fosamprenavir
Indinavir	204% ↑ in AUC	32%↓ in AUC
Lopinavir/ritonavir	5.7-fold ↑ AUC, 3.4 fold ↑ Cmax	No significant change in lopinavir kinetics.	Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted. Further dosage reduction of rifabutin may be necessary.
Saquinavir	ND	40% ↓ in AUC
Ritonavir	4 fold increase in AUC, 2.5 fold increase in Cmax	ND	In the presence of ritonavir the subsequent risk of side effects, including uveitis may be increased . If a protease inhibitor is required in a patient treated with rifabutin, agents other than ritonavir should be considered.
Tipranavir/ritonavir[133]	2.9-fold ↑ AUC, 1.7-fold ↑ Cmax	No significant change in tipranavir kinetics.	Therapeutic drug monitoring of rifabutin is recommended.
Zidovudine	No significant change in kinetics.	Approximately 32%↓ in Cmax and AUC	A large controlled clinical study has shown that these changes are of no clinical relevance.
ANTIFUNGALS
ANTIFUNGALS	82% ↑ in AUC	No significant change in steady-state plasma concentrations
Itraconazole	ND	70% to 75% ↓ in Cmax and AUC	One case report suggests a kinetic interaction resulting in an increase in serum rifabutin levels and a risk for developing uveitis in the presence of itraconazole.
Posaconazole	31%↑ Cmax, 72%↑ AUC	43%↓ Cmax, 49%↓ AUC	If the drugs are co-administered, patients should be monitored for adverse events associated with rifabutin administration.
Voriconazole	195%↑ Cmax, 331%↑ AUC - voriconazole dosed at 400 mg twice daily	Rifabutin (300 mg once daily) decreased the Cmax and AUC of voriconazole at 200 mg twice daily by 69% and 78%, respectively. During co-administration with rifabutin, the Cmax and AUC of voriconazole at 350 mg twice daily were 96% and 68% of the levels when administered alone at 200 mg twice daily. At a voriconazole dose of 400 mg twice daily Cmax and AUC were 104% and 87% higher, respectively, compared with voriconazole alone at 200 mg twice daily.	If the benefit outweighs the risk, rifabutin may be coadministered with voriconazole if the maintenance dose of voriconazole is increased to 5 mg/kg intravenously every 12 hours or from 200 mg to 350 mg orally, every 12 hours (100 mg to 200 mg orally, every 12 hours in patients less than 40 kg). Careful monitoring of full blood counts and adverse events to rifabutin (e.g. uveitis) is recommended when rifabutin is coadministered with voriconazole
ANTI-PCP (Pneumocystis carinii pneumonia)
Dapsone	ND	Approximately 27% to 40% ↓ in AUC	Study conducted in HIV infected patients (rapid and slow acetylators).
Sulfamethoxazole-Trimethoprim	No significant change in Cmax and AUC	Approximately 15% to 20% ↓ in AUC	In another study, only trimethoprim (not sulfamethoxazole) had 14% ↓ in AUC and 6%↓ in Cmax but were not considered clinically significant.
ANTI-MAC (Mycobacterium avium intracellulare complex)
Azithromycin	No PK interaction	No PK interaction
Clarithromycin	Approximately 77% ↑ in AUC	Approximately 50%↓ in AUC	Study conducted in HIV infected patients. Dose of rifabutin should be adjusted in the presence of clarithromycin
ANTI-TB (Tuberculosis)
Ethambutol	ND	No significant change in AUC or Cmax
Isoniazid	ND	Pharmacokinetics not affected
Pyrazinamide	ND	ND	Study data being evaluated.
OTHER
Methadone	ND	No significant effect	No apparent effect of rifabutin on either peak levels of methadone or systemic exposure based upon AUC. Rifabutin kinetics not evaluated.
Ethinylestradiol	ND	35%↓ AUC 20%↓ Cmax	Patients should be advised to use other methods of contraception.
Norethindrone	ND	46%↓ AUC	Patients should be advised to use other methods of contraception.
Tacrolimus	ND	ND	Authors report that rifabutin decreases tacrolimus trough blood levels.
Theophylline	ND	No significant change in AUC or Cmax compared with baseline.

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Table 8: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2) ]
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.9) ].
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.11) and Use in Specific Populations (8.5) ].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs [see Adverse Reactions (6.1) ].
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anticoagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions (5.15) ].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution Two-fold increase in exposure	Monitor for sildenafil toxicity [see Clinical Pharmacology (12.3) ].
Duloxetine	Avoid Use Five-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity.
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs that Interfere with Hemostasis
Clinical Impact :	Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention :	Monitor patients with concomitant use of Meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact :	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention :	Concomitant use of Meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors , Angiotensin Receptor Blockers , or Beta - Blockers
Clinical Impact :	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention :	During concomitant use of Meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of Meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact :	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention :	During concomitant use of Meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Lithium
Clinical Impact :	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology (12.3)].
Intervention :	During concomitant use of Meloxicam and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact :	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention :	During concomitant use of Meloxicam and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact :	Concomitant use of Meloxicam and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention :	During concomitant use of Meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact :	Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention :	The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact :	Concomitant use of Meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention :	During concomitant use of Meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.

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Table 8:Effect of Voriconazole on Pharmacokinetics of Other Drugs [ see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C_max and AUC_τ)	Recommendations for Drug Dosage Adjustment/Comments
* Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects * Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30-100 mg q24h) ** Non-Steroidal Anti-Inflammatory Drug *** Non-Nucleoside Reverse Transcriptase Inhibitors
Sirolimus* (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin* (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (400 mg q24h)** (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (300 mg q24h)** (CYP3A4 Inhibition)	Slight Increase in AUC_τ	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)** (CYP3A4 Inhibition)	No Significant Effect of Voriconazole on Ritonavir Cmax or AUC_τ	Contraindicated because of significant reduction of voriconazole Cmax and AUCτ

Low-dose Ritonavir (100 mg q12h)**	Slight Decrease in Ritonavir Cmax and AUCτ	Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole Cmax and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated
Cyclosporine* (CYP3A4 Inhibition)	AUC_τ Significantly Increased; No Significant Effect on C_max	When initiating therapy with voriconazole tablets in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole tablets are discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
Methadone*** (CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole tablets. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7)]
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole tablets. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see Drug Interactions (7)].
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole tablets. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7)].
NSAIDs**** including. ibuprofen and diclofenac (CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [see Drug Interactions (7)].
Tacrolimus* (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with voriconazole tablets in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole tablets are discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin* (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)**	Increased	Monitoring for adverse events related to oral contraceptives is recommended during coadministration
Warfarin* (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole* (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with voriconazole tablets in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects on Indinavir Exposure In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	No dosage adjustment for indinavir when coadministered with voriconazole tablets Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIs***** (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.
Everolimus (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Concomitant administration of voriconazole and everolimus is not recommended.

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Table 3: Clinically Significant Drug Interactions with Celecoxib
Drugs That Interfere w ith Hemostasis
Clinical Impact:	Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of Celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of celecoxib with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11) ].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2) ]. In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200 to 400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100 to 325 mg).
Intervention:	Concomitant use of celecoxib and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11) ]. Celecoxib is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of celecoxib and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of celecoxib and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6) ]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of celecoxib with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6) ].
Digoxin
Clinical Impact:	The concomitant use of Celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of celecoxib and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of celecoxib and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Celecoxib has no effect on methotrexate pharmacokinetics.
Intervention:	During concomitant use of celecoxib and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of celecoxib and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of celecoxib and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs a nd Salicylates
Clinical Impact:	Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2) ].
Intervention:	The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of celecoxib and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of celecoxib and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or inducers
Clinical Impact:	Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib.
Intervention	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [see Clinical Pharmacology (12.3) ].
CYP2D6 substrates
Clinical Impact:	In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs.
Intervention	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [see Clinical Pharmacology (12.3) ].
Corticosteroids
Clinical Impact:	Concomitant use of corticosteroids with celecoxib may increase the risk of GI ulceration or bleeding.
Intervention	Monitor patients with concomitant use of celecoxib with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2) ].

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Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9Hydroxy- Risperidone (RatioChange relative to reference)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 3: Clinically Relevant Interactions Affecting Drugs Co-Administered with Omeprazole and Interaction with Diagnostics
Antiretrovirals
Clinical Impact:	The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology ( 12.3)]. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)]. There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
Intervention:	Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications ( 4)] . Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:	Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention:	Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact:	Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions ( 5.11)].
Intervention:	A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact:	Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology ( 12.3)]. There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel .
Intervention:	Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions ( 5.6)].
Citalopram
Clinical Impact:	Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology ( 12.3)] .
Intervention:	Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:	Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology ( 12.3)].
Intervention:	Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:	Potential for increased exposure of phenytoin.
Intervention:	Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:	Increased exposure of diazepam [see Clinical Pharmacology ( 12.3)] .
Intervention:	Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:	Potential for increased exposure of digoxin [see Clinical Pharmacology ( 12.3)].
Intervention:	Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:	Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:	Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology ( 12.3)] . See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:	Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:	See Contraindications, Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact:	Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19 .
Intervention:	Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:	Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions ( 5.10), Clinical Pharmacology ( 12.2)] .
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:	Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology ( 12.2)] .
False Positive Urine Tests for THC
Clinical Impact:	There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:	An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:	There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:	Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.

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Drugs That Interfere with Hemostasis
Clinical Impact:	• Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	• During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

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DRUG	DESCRIPTION OF INTERACTION
Sulfonylureas	Hypoglycemia potentiated.
Methotrexate	Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants	Increased bleeding.

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Antiretrovirals
Clinical Impact:	The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. • Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3)]. • Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)]. • There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
Intervention:	Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications (4)]. Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:	Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention:	Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact:	Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].
Intervention:	A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact:	Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)]. There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention:	Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6)].
Citalopram
Clinical Impact:	Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention:	Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:	Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].
Intervention:	Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:	Potential for increased exposure of phenytoin.
Intervention:	Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:	Increased exposure of diazepam [see Clinical Pharmacology (12.3)].
Intervention:	Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:	Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention:	Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:	Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:	Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)]. See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:	Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:	See Contraindications, Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact:	Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention:	Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:	Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10),Clinical Pharmacology (12.2)].
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:	Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact:	There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:	An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:	There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:	Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.

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Table 4: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin extended-release tablets is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline	Avoid use (Plasma exposure likely to be increased and prolonged)	Concurrent administration of ciprofloxacin extended-release tablets with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.9) ].
Drugs Known to Prolong QT Interval	Avoid use	Ciprofloxacin extended-release tablets may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.11) and Use in Specific Populations (8.5)].
Oral Antidiabetic Drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin extended-release tablets and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin extended-release tablets are co-administered with oral antidiabetic drugs [see Adverse Reactions (6.1)].
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin extended-release tablets discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin extended-release tablets with phenytoin.
Cyclosporine	Use with caution (Transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin extended-release tablets are co-administered with cyclosporine.
Anticoagulant Drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin extended-release tablets to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin extended-release tablets with an oral anticoagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin extended-release tablets therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin extended-release tablets [see Warnings and Precautions (5.15)].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin extended-release tablets is advised.
NSAIDs	Use with caution	Nonsteroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution 2-fold increase in exposure	Monitor for sildenafil toxicity [see Clinical Pharmacology (12.3) ].
Duloxetine	Avoid use 5-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity.
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin extended-release tablets inhibit the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin Extended-Release Tablets
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx^® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin extended-release tablets should be taken at least 2 hours before or 6 hours after multivalent cation-containing products administration [see Dosage and Administration (2)]	Decrease ciprofloxacin extended-release tablets absorption, resulting in lower serum and urine levels considerably lower than desired for concurrent administration of these agents with ciprofloxacin extended-release.
Probenecid	Use with caution (Interferes with renal tubular secretion of ciprofloxacin extended-release tablets and increases ciprofloxacin extended-release tablets serum levels)	Potentiation of ciprofloxacin extended-release tablets toxicity may occur.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion–the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide(including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide(including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄, and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5’-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.

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Table 2: Clinically Significant Drug Interactions with Diclofenac
Drugs That Interfere with Hemostasis
Clinical Impact:	Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of diclofenac with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding ( see PRECAUTIONS; Hematological Toxicity ).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation) .
Intervention:	Concomitant use of diclofenac and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding ( see PRECAUTIONS: Hematological Toxicity ). Diclofenac is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible
Intervention:	During concomitant use of diclofenac and ACE-inhibitors, ARBs, or betablockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of diclofenac and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function ( see WARNINGS; Renal Toxicity and Hyperkalemia ). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of diclofenac with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects ( see WARNINGS; Renal Toxicity and Hyperkalemia ).
Digoxin
Clinical Impact:	The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of diclofenac and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of diclofenac and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of diclofenac and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of diclofenac and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention:	During concomitant use of diclofenac and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy ( see WARNINGS; Gastrointestinal Bleeding, Ulceration, and Perforation ).
Intervention:	The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of diclofenac and pemetrexed may increase the risk of pemetrexedassociated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of diclofenac and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or Inducers:
Clinical Impact:	Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Co-administration of diclofenac with CYP2C9 inhibitors (e.g. voriconazole) may enhance the exposure and toxicity of diclofenac whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of diclofenac.
Intervention:	A dosage adjustment may be warranted when diclofenac is administered with CYP2C9 inhibitors or inducers ( see CLINICAL PHARMACOLOGY; Pharmacokinetics ).

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Drugs That Interfere with Hemostasis
Clinical Impact	Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention	Monitor patients with concomitant use of diclofenac sodium topical solution with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)]
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of NSAID alone [see Warnings and Precautions (5.2)]
Intervention	Concomitant use of diclofenac sodium topical solution and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Diclofenac sodium topical solution is not a substitute for low dose aspirin for cardiovascular protection.
ACE inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:		NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:		During concomitant use of diclofenac sodium topical solution and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of diclofenac sodium topical solution and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions(5.6)] When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:		Clinical studies, as well as post-marketing observations, showed that NSAIDS reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:		During concomitant use of diclofenac sodium topical solution with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact:		The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life digoxin.
Intervention:		During concomitant use of diclofenac sodium topical solution and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:		NSAIDS have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:		During concomitant use of diclofenac sodium topical solution and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact;		Concomitant use of NSAIDs and methotrexate may increase the risk of methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:		During concomitant use of diclofenac sodium topical solution and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:		Concomitant use of diclofenac sodium topical solution and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:		During concomitant use of diclofenac sodium topical solution and cyclosporine, monitor patients for signs or worsening renal function.
NSAIDs and Salicylates
Clinical Impact:		Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Concomitant use of oral NSAIDs with diclofenac sodium topical solution has been evaluated in one Phase 3 controlled trial and in combination with oral diclofenac, compared to oral diclofenac alone, resulted in a higher rate of rectal hemorrhage (3% vs. less than 1%), and more frequent abnormal creatinine (12% vs. 7%), urea (20% vs. 12%) and hemoglobin (13% vs. 9%).
Intervention:		The concomitant use of diclofenac with other NSAIDs or salicyclates is not recommended. Do not use combination therapy with diclofenac sodium topical solution and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations
Pemetrexed
Clinical Impact:		Concomitant use of diclofenac sodium topical solution and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:		During concomitant use of diclofenac sodium topical solution and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives 9e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.

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Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C_max and AUCτ)	Recommendations for Drug Dosage Adjustment/Comments
Sirolimus* (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin* (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (400 mg q 24h) (CYP3A4 Inhibition) Efavirenz (300 mg q 24h) (CYP3A4 Inhibition)	Significantly Increased Slight decrease in AUC_t	Contraindicated When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)**(CYP3A4 Inhibition)	No Significant Effect of Voriconazole on Ritonavir C_max or AUCτ	Contraindicated because of significant reduction of voriconazole C_max and AUCτ
Low-dose Ritonavir (100 mg q12h)**	Slight Decrease in Ritonavir C_max and AUCτ	Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole C_max and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated
Cyclosporine* (CYP3A4 Inhibition)	AUCτ Significantly Increased; No Significant Effect on C_max	When initiating therapy with voriconazole in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
Methadone*** (CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7) ]
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see Drug Interactions (7) ].
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7) ].
NSAIDs**** including ibuprofen and diclofenac (CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed. [see Drug Interactions (7) ].
Tacrolimus* (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with voriconazole in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin* (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)**	Increased	Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin* (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	Monitor PT or other suitable anticoagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole* (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with voriconazole in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects on Indinavir Exposure	No dosage adjustment for indinavir when coadministered with voriconazole
	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIs***** (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.
Everolimus (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Concomitant administration of voriconazole and everolimus is not recommended

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Inhibitors of CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6
Clinical Impact:	Methadone undergoes hepatic N-demethylation by several cytochrome P450 (CYP) isoforms, including CYP3A4, CYP2B6, CYP2C19, CYP2C9, and CYP2D6. The concomitant use of methadone hydrochloride tablets for oral suspension and CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors can increase the plasma concentration of methadone, resulting in increased or prolonged opioid effects, and may result in a fatal overdose, particularly when an inhibitor is added after a stable dose of methadone hydrochloride tablets for oral suspension is achieved. These effects may be more pronounced with concomitant use of drugs that inhibit more than one of the CYP enzymes listed above. After stopping a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitor, as the effects of the inhibitor decline,
	the methadone plasma concentration can decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or withdrawal symptoms in patients physically dependent on methadone.
Intervention:	If concomitant use is necessary, consider dosage reduction of methadone hydrochloride tablets for oral suspension until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitor is discontinued, follow patients for signs of opioid withdrawal and consider increasing the methadone hydrochloride tablets for oral suspension dosage until stable drug effects are achieved.
Examples:	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir), fluconazole, fluvoxamine, some selective serotonin reuptake inhibitors (SSRIs) (e.g., sertraline, fluvoxamine)
Inducers of CYP3A4, CYP2B6, CYP2C19, or CYP2C9
Clinical Impact:	The concomitant use of methadone hydrochloride tablets for oral suspension and CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers can decrease the plasma concentration of methadone [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of withdrawal symptoms in patients physically dependent on methadone. These effects could be more pronounced with concomitant use of drugs that can induce multiple CYP enzymes. After stopping a CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducer, as the effects of the inducer decline, the methadone plasma concentration can increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression, sedation, or death.
Intervention:	If concomitant use is necessary, consider increasing the methadone hydrochloride tablets for oral suspension dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducer is discontinued, consider methadone hydrochloride tablets for oral suspension dosage reduction and monitor for signs of respiratory depression and sedation.
Examples:	Rifampin, carbamazepine, phenytoin, St. John’s Wort, Phenobarbital
Potentially Arrhythmogenic Agents
Clinical Impact:	Pharmacodynamic interactions may occur with concomitant use of methadone and potentially arrhythmogenic agents or drugs capable of inducing electrolyte disturbances (hypomagnesemia, hypokalemia).
Intervention:	Monitor patients closely for cardiac conduction changes.
Examples:	Drugs known to have potential to prolong QT interval: Class I and III antiarrhythmics, some neuroleptics and tricyclic antidepressants, and calcium channel blockers. Drugs capable of inducing electrolyte disturbances: Diuretics, laxatives, and, in rare cases, mineralocorticoid hormones.
Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of CNS depressants can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Consider dose reduction of one or both drugs. Monitor patients for respiratory depression, sedation, and hypotension [see Warnings and Precautions (5.8)].
Examples:	Alcohol, benzodiazepines, and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions (5.9)].
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue methadone hydrochloride tablets for oral suspension if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT₃receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.1)].
Intervention:	The use of methadone hydrochloride tablets for oral suspension is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	Patients maintained on methadone may experience withdrawal symptoms when given opioid antagonists, mixed agonist/antagonists, and partial agonists.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Methadone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of methadone hydrochloride tablets for oral suspension and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when methadone hydrochloride tablets for oral suspension is used concomitantly with anticholinergic drugs.

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Table 1: Clinically Significant Drug Interactions with Piroxicam
Drugs That Interfere with Hemostasis
Clinical Impact:	( Piroxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of piroxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. ( Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of Piroxicam Capsules USP with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention:	Concomitant use of Piroxicam Capsules USP and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Piroxicam Capsules USP is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors , Angiotensin Receptor Blockers , and Beta - Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of Piroxicam Capsules USP and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of Piroxicam Capsules USP and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of Piroxicam Capsules USP with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact:	The concomitant use of piroxicam with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of Piroxicam Capsules USP and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of Piroxicam Capsules USP and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of Piroxicam Capsules USP and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of Piroxicam Capsules USP and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of Piroxicam Capsules USP and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of piroxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention:	The concomitant use of piroxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of Piroxicam Capsules USP and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of Piroxicam Capsules USP and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Highly Protein Bound Drugs
Clinical Impact:	Piroxicam Capsules USP is highly protein bound and, therefore, might be expected to displace other protein bound drugs.
Intervention:	Physicians should closely monitor patients for a change in dosage requirements when administering Piroxicam Capsules USP to patients on other highly protein bound drugs.
Corticosteroids
Clinical Impact:	Concomitant use of corticosteroids with Piroxicam Capsules USP may increase the risk of GI ulceration or bleeding.
Intervention:	Monitor patients with concomitant use of Piroxicam Capsules USP with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)].

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Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
*Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	Cmax
Enzyme (CYP2D6) inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not Needed

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine	Do not exceed 10 mg atorvastatin daily
Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir)	Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used.

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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NA – Not available/reported
Digoxin concentrations increased greater than 50%
	Digoxin Serum Concentration Increase	Digoxin AUC Increase	Recommendations
Amiodarone	70%	NA	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
Captopril	58%	39%
Clarithromycin	NA	70%
Dronedarone	NA	150%
Gentamicin	129-212%	NA
Erythromycin	100%	NA
Itraconazole	80%	NA
Nitrendipine	57%	15%
Propafenone	NA	60-270%
Quinidine	100%	NA
Ranolazine	50%	NA
Ritonavir	NA	86%
Tetracycline	100%	NA
Verapamil	50-75%	NA
Digoxin concentrations increased less than 50%
Atorvastatin	22%	15%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
Carvedilol	16%	14%
Diltiazem	20%	NA
Indomethacin	40%	NA
Nefazodone	27%	15%
Nifedipine	45%	NA
Propantheline	24%	24%
Quinine	NA	33%
Saquinavir	27%	49%
Spironolactone	25%	NA
Telmisartan	20-49%	NA
Tolvaptan	30%	NA
Trimethoprim	22-28%	NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole, rabeprazole,			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate, sulfasalazine			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20-40% as necessary.
No significant Digoxin exposure changes
Please refer to section 12 for a complete list of drugs which were studied but reported no significant changes on digoxin exposure.			No additional actions are required.

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Antiretrovirals
Clinical Impact:	The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology ( 12.3)] . Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology ( 12.3)] . There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
Intervention:	Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications ( 4)] . Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:	Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention:	Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact:	Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions ( 5.11)] .
Intervention:	A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact:	Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology ( 12.3)] . There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention:	Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions ( 5.6)] .
Citalopram
Clinical Impact:	Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology ( 12.3)] .
Intervention:	Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:	Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology ( 12.3)] .
Intervention:	Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:	Potential for increased exposure of phenytoin.
Intervention:	Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:	Increased exposure of diazepam [see Clinical Pharmacology ( 12.3)] .
Intervention:	Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:	Potential for increased exposure of digoxin [see Clinical Pharmacology ( 12.3)] .
Intervention:	Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:	Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:	Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology ( 12.3)] . See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:	Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated.
	Amoxicillin also has drug interactions.
Intervention:	See Contraindications, Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact:	Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention:	Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:	Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions ( 5.10), Clinical Pharmacology ( 12.2)] .
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:	Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology ( 12.2)] .
False Positive Urine Tests for THC
Clinical Impact:	There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:	An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:	There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:	Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.

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Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	The concomitant use of SSRIs including sertraline hydrochloride and MAOIs increases the risk of serotonin syndrome.
Intervention:	Sertraline hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [See Dosage and Administration (2.5), Contraindications (4), Warnings and Precautions (5.2)].
Examples:	selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
Pimozide
Clinical Impact:	Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QT prolongation and ventricular arrhythmias.
Intervention:	Concomitant use of pimozide and sertraline hydrochloride is contraindicated [See Contraindications (4)].
Other Serotonergic Drugs
Clinical Impact:	The concomitant use of serotonergic drugs with sertraline hydrochloride increases the risk of serotonin syndrome.
Intervention:	Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of sertraline hydrochloride and/or concomitant serotonergic drugs [See Warnings and Precautions (5.2)].
Examples:	other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort
Drugs that Interfere with Hemostasis (antiplatelet agents and anticoagulants)
Clinical Impact:	The concurrent use of an antiplatelet agent or anticoagulant with sertraline hydrochloride may potentiate the risk of bleeding.
Intervention:	Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [See Warnings and Precautions (5.3)].
Examples:	aspirin, clopidogrel, heparin, warfarin
Drugs Highly Bound to Plasma Protein
Clinical Impact:	Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of sertraline hydrochloride with another drug that is highly bound to plasma protein may increase free concentrations of sertraline hydrochloride or other tightly-bound drugs in plasma [See Clinical Pharmacology (12.3)].
Intervention:	Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs as warranted.
Examples:	warfarin
Drugs Metabolized by CYP2D6
Clinical Impact:	Sertraline hydrochloride is a CYP2D6 inhibitor [See Clinical Pharmacology (12.3)]. The concomitant use of sertraline hydrochloride with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate.
Intervention:	Decrease the dosage of a CYP2D6 substrate if needed with concomitant sertraline hydrochloride use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride is discontinued.
Examples:	propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine
Phenytoin
Clinical Impact:	Phenytoin is a narrow therapeutic index drug. sertraline hydrochloride may increase phenytoin concentrations.
Intervention:	Monitor phenytoin levels when initiating or titrating sertraline hydrochloride. Reduce phenytoin dosage if needed.
Examples:	phenytoin, fosphenytoin

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NA = Not available/reported
Digoxin concentrations increased greater than 50%
	Digoxin Serum Concentration Increase	Digoxin AUC Increase	Recommendations
Amiodarone	70%	NA	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
Captopril	58%	39%
Clarithromycin	NA	70%
Dronedarone	NA	150%
Gentamicin	129-212%	NA
Erythromycin	100%	NA
Itraconazole	80%	NA
Lapatinib	NA	180%
Nitrendipine	57%	15%
Propafenone	NA	60-270%
Quinidine	100%	NA
Ranolazine	50%	NA
Ritonavir	NA	86%
Telaprevir	50%	85%
Tetracycline	100%	NA
Verapamil	50-75%	NA
Digoxin concentrations increased less than 50%
Atorvastatin	22%	15%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
Carvedilol	16%	14%
Conivaptan	33%	43%
Diltiazem	20%	NA
Indomethacin	40%	NA
Nefazodone	27%	15%
Nifedipine	45%	NA
Propantheline	24%	24%
Quinine	NA	33%
Rabeprazole	29%	19%
Saquinavir	27%	49%
Spironolactone	25%	NA
Telmisartan	20-49%	NA
Ticagrelor	31%	28%
Tolvaptan	30%	20%
Trimethoprim	22-28%	NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate and sulfasalazine			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20-40% as necessary.

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Bleeding times
Clinical Impact:	Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention:	This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact:	The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention:	Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact:	Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention:	This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.

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Calcium Channel Blockers	Antifungals	Antibiotics	Glucocorticoids	Other Drugs
diltiazem	fluconazole	azithromycin	methylprednisolone	Allopurinol
nicardipine	itraconazole	clarithromycin		Amiodarone
verapamil	ketoconazole	erythromycin		Bromocriptine
	voriconazole	quinupristin/ dalfopristin		colchicine
				danazol
				imatinib
				metoclopramide
				nefazodone
				oral contraceptives

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Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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¹ = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. ² = Is not administered but is an active metabolite of carbamazepine. NC=Less than 10% change in plasma concentration NE=Not Evaluated
AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase ¹	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide ²	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Drugs That May Increase the Risk of Hypoglycemia
Drugs:	Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin analog (e.g., octreotide), and sulfonamide antibiotics.
Intervention:	Dose adjustment and increased frequency of glucose monitoring may be required when NOVOLOG is co-administered with these drugs.
Drugs That May Decrease the Blood Glucose Lowering Effect of NOVOLOG
Drugs:	Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones.
Intervention:	Dose adjustment and increased frequency of glucose monitoring may be required when NOVOLOG is co-administered with these drugs.
Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of NOVOLOG
Drugs:	Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.
Intervention:	Dose adjustment and increased frequency of glucose monitoring may be required when NOVOLOG is co-administered with these drugs.
Drugs That May Blunt Signs and Symptoms of Hypoglycemia
Drugs:	Beta-blockers, clonidine, guanethidine and reserpine
Intervention:	Increased frequency of glucose monitoring may be required when NOVOLOG is co-administered with these drugs.

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Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
StrongCYP3A4Inhibitors (e.g.,itraconazole,clarithromycin) or strongCYP2D6inhibitors (e.g.,quinidine,fluoxetine,paroxetine)	The concomitant use of aripiprazole tablets withstrong CYP3A4 orCYP2D6inhibitorsincreasedthe exposure ofaripiprazole tabletscomparedto the use of aripiprazole tabletsalone[seeCLINICALPHARMACOLOGY(12.3)].	Withconcomitant use of aripiprazole tablets with a strongCYP3A4inhibitororCYP2D6inhibitor, reducethearipiprazole tablets dosage[see DOSAGEANDADMINISTRATION(2.7)].
StrongCYP3A4Inducers (e.g.,carbamazepine,rifampin)	The concomitant use of aripiprazole tabletsandcarbamazepine decreased the exposure of aripiprazole tablets compared to the use of aripiprazole tablets alone [see CLINICALPHARMACOLOGY(12.3)].	Withconcomitant use of aripiprazole tablets with a strongCYP3A4inducer, consider increasing the aripiprazole tabletsdosage[see DOSAGE ANDADMINISTRATIO(2.7)].
AntihypertensiveDrugs	Duetoitsalphaadrenergicantagonism,aripiprazole tablets hasthepotentialtoenhance the effect of certainantihypertensive agents.	Monitor bloodpressureand adjustdoseaccordingly[seeWARNINGS AND PRECAUTIONS(5.7)].
Benzodiazepines(e.g., lorazepam)	Theintensityofsedationwas greaterwith the combination of oral aripiprazole tabletsandlorazepam as comparedtothat observedwith aripiprazole alone.Theorthostatichypotension observed wasgreaterwith the combination as comparedtothatobserved withlorazepamalone[seeWARNINGSANDPRECAUTIONS(5.7)]	Monitorsedation and blood pressure.Adjust dose accordingly.

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Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy-Risperidone (Ratio*)		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	C_max
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed

Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Table 8: Selected Drug Interactions in Adults
Concomitant Drug Class: Drug Name	Effect on Concentration of Raltegravir	Clinical Comment
Metal-Containing Antacids
aluminum and/or magnesium-containing antacids	↓	Coadministration or staggered administration of aluminum and/or magnesium hydroxide-containing antacids and ISENTRESS is not recommended.
Other Agents
rifampin	↓	The recommended dosage of ISENTRESS is 800 mg twice daily during coadministration with rifampin. There are no data to guide co-administration of ISENTRESS with rifampin in patients below 18 years of age [see Dosage and Administration (2.1)].

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cation or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products.
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agent	Carefully monitor blood glucose (5.11, 7.3)

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Table 3: Clinically Significant Drug Interactions with Celecoxib
Drugs That Interfere w ith Hemostasis
Clinical Impact:	Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of Celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of celecoxib with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11) ].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2) ]. In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200 to 400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100 to 325 mg).
Intervention:	Concomitant use of celecoxib and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11) ]. Celecoxib is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of celecoxib and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of celecoxib and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6) ]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of celecoxib with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6) ].
Digoxin
Clinical Impact:	The concomitant use of Celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of celecoxib and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of celecoxib and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Celecoxib has no effect on methotrexate pharmacokinetics.
Intervention:	During concomitant use of celecoxib and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of celecoxib and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of celecoxib and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs a nd Salicylates
Clinical Impact:	Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2) ].
Intervention:	The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of celecoxib and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of celecoxib and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or inducers
Clinical Impact:	Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib.
Intervention	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [see Clinical Pharmacology (12.3) ].
CYP2D6 substrates
Clinical Impact:	In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs.
Intervention	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [see Clinical Pharmacology (12.3) ].
Corticosteroids
Clinical Impact:	Concomitant use of corticosteroids with celecoxib may increase the risk of GI ulceration or bleeding.
Intervention	Monitor patients with concomitant use of celecoxib with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2) ].

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine, danazol	Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem	Do not exceed 40 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
↓= Decreased (induces lamotrigine gluronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ?= Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
	? CBZ epoxide	May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 3: Drugs Affected by Phenytoin
* The effect of phenytoin on phenobarbital, valproic acid and sodium valproate serum levels is unpredictable
Interacting Agent	Examples
Drugs whose efficacy is impaired by phenytoin
Azoles	Fluconazole, ketoconazole, itraconazole, posaconazole, voriconazole
Antineoplastic agents	Irinotecan, paclitaxel, teniposide
Delavirdine	Phenytoin can substantially reduce the concentrations of delavirdine. This can lead to loss of virologic response and possible resistance [see Contraindications (4)].
Neuromuscular blocking agents	Cisatracurium, pancuronium, rocuronium and vecuronium: resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents has occurred in patients chronically administered phenytoin. Whether or not phenytoin has the same effect on other non-depolarizing agents is unknown. Prevention or Management: Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher.
Warfarin	Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin
Other	Corticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D
Drugs whose level is decreased by phenytoin
Antiepileptic drugs*	Carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine,
Antilipidemic agents	Atorvastatin, fluvastatin, simvastatin
Antiviral agents	Efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir Fosamprenavir: phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir
Calcium channel blockers	Nifedipine, nimodipine, nisoldipine, verapamil
Other	Albendazole (decreases active metabolite), chlorpropamide, clozapine, cyclosporine, digoxin, folic acid, methadone, mexiletine, praziquantel, quetiapine

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Antibiotics	Anticonvulsants	Other Drugs/Dietary Supplements
nafcillin	carbamazepine	bosentan
rifampin	oxcarbazepine	octreotide
	phenobarbital	orlistat
	phenytoin	sulfinpyrazone
		terbinafine
		ticlopidine
		St. John's Wort

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Drugs that Affect Renal Function	A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDs], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics	Dofetilide	Concomitant administration with digoxin was associated with a higher rate of torsades de pointes.
	Sotalol	Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
	Dronedarone	Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog	Teriparatide	Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement	Thyroid	Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics	Epinephrine Norepinephrine Dopamine	Can increase the risk of cardiac arrhythmias.
Neuromuscular Blocking Agents	Succinylcholine	May cause sudden extrusion of potassium from muscle cells, causing arrhythmias in patients taking digoxin.
Supplements	Calcium	If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers		Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.
Ivabradine	Can increase the risk of bradycardia.

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Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Table 7: Summary of AED Interactions with Oxcarbazepine
¹nc denotes a mean change of less than 10%
²Pediatrics
³Mean increase in adults at high oxcarbazepine doses
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400 to 2000	900	nc ¹	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100 to150	600 to 1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250 to 500	600 to 1800 >1200 to 2400	nc ^1,2 up to 40% increase ³ [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400 to 2800	600 to 1800	nc ¹	18% decrease [CI: 13% decrease, 40% decrease]
Lamotrigine	200	1200	nc ¹	nc ¹

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Table 5. Clinically-Significant Drug Interactions with Sertraline Hydrochloride
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	The concomitant use of SSRIs including sertraline hydrochloride and MAOIs increases the risk of serotonin syndrome.
Intervention:	Sertraline hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [See Dosage and Administration (2.5), Contraindications (4), Warnings and Precautions (5.2)].
Examples:	selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
Pimozide
Clinical Impact:	Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QT prolongation and ventricular arrhythmias.
Intervention:	Concomitant use of pimozide and sertraline hydrochloride is contraindicated [See Contraindications (4)].
Other Serotonergic Drugs
Clinical Impact:	The concomitant use of serotonergic drugs with sertraline hydrochloride increases the risk of serotonin syndrome.
Intervention:	Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of sertraline hydrochloride and/or concomitant serotonergic drugs [See Warnings and Precautions (5.2)].
Examples:	other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort
Drugs that Interfere with Hemostasis (antiplatelet agents and anticoagulants)
Clinical Impact:	The concurrent use of an antiplatelet agent or anticoagulant with sertraline hydrochloride may potentiate the risk of bleeding.
Intervention:	Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [See Warnings and Precautions (5.3)].
Examples:	aspirin, clopidogrel, heparin, warfarin
Drugs Highly Bound to Plasma Protein
Clinical Impact:	Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of sertraline hydrochloride with another drug that is highly bound to plasma protein may increase free concentrations of sertraline hydrochloride or other tightly-bound drugs in plasma [See Clinical Pharmacology (12.3)] .
Intervention:	Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs as warranted.
Examples:	warfarin
Drugs Metabolized by CYP2D6
Clinical Impact:	Sertraline hydrochloride is a CYP2D6 inhibitor [See Clinical Pharmacology (12.3)] . The concomitant use of sertraline hydrochloride with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate.
Intervention:	Decrease the dosage of a CYP2D6 substrate if needed with concomitant sertraline hydrochloride use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride is discontinued.
Examples:	propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine
Phenytoin
Clinical Impact:	Phenytoin is a narrow therapeutic index drug. Sertraline hydrochloride may increase phenytoin concentrations.
Intervention:	Monitor phenytoin levels when initiating or titrating sertraline hydrochloride. Reduce phenytoin dosage if needed.
Examples:	phenytoin, fosphenytoin

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Interacting DrugInteracting Drug	InteractionInteraction
Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.12, 7.3)

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* The effect of phenytoin on phenobarbital, valproic acid and sodium valproate serum levels is unpredictable
Interacting Agent	Examples
Drugs whose efficacy is impaired by phenytoin
Azoles	Fluconazole, ketoconazole, itraconazole, posaconazole, voriconazole
Antineoplastic agents	Irinotecan, paclitaxel, teniposide
Delavirdine	Phenytoin can substantially reduce the concentrations of delavirdine. This can lead to loss of virologic response and possible resistance [see Contraindications (4)].
Neuromuscular blocking agents	Cisatracurium, pancuronium, rocuronium and vecuronium: resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents has occurred in patients chronically administered phenytoin. Whether or not phenytoin has the same effect on other non-depolarizing agents is unknown. Prevention or Management: Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher.
Warfarin	Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin
Other	Corticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D
Drugs whose level is decreased by phenytoin
Antiepileptic drugs*	Carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine,
Antilipidemic agents	Atorvastatin, fluvastatin, simvastatin
Antiviral agents	Efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir Fosamprenavir: phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir
Calcium channel blockers	Nifedipine, nimodipine, nisoldipine, verapamil
Other	Albendazole (decreases active metabolite), chlorpropamide, clozapine, cyclosporine, digoxin, folic acid, methadone, mexiletine, praziquantel, quetiapine

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine concentrations approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine and carbamazepine epoxide	? carbamazepine epoxide	May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2 fold.
Valproate	? valproate	There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Table 6: Clinically Significant Drug Interactions with Paricalcitol
CYP3A Inhibitors
Clinical Impact	Paricalcitol is partially metabolized by CYP3A. Hence, exposure of paricalcitol will increase upon coadministration with strong CYP3A inhibitors such as but not limited to: boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole.
Intervention	Dose adjustment of paricalcitol capsules may be necessary. Monitor closely for iPTH and serum calcium concentrations, if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor.
Cholestyramine
Clinical Impact	Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of paricalcitol.
Intervention	Recommend to take paricalcitol capsules at least 1 hour before or 4 to 6 hours after taking cholestyramine (or at as great an interval as possible) to avoid impeding absorption of paricalcitol.
Mineral Oil
Clinical Impact	Mineral oil or other substances that may affect absorption of fat may influence the absorption of paricalcitol.
Intervention	Recommend to take paricalcitol capsules at least 1 hour before or 4 to 6 hours after taking mineral oil (or at as great an interval as possible) to avoid affecting absorption of paricalcitol.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. ₄ ₃
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT , is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. ₄ ₄ ₄ ₄ ₃ ₄ ₄ ₄
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. ₄
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T to T , leading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T and T levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). ₄ ₃ ₃ ₄ ₃ ₄ ₃ ₄ ₃ ₄
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of I, I, and Tc. ¹²³ ¹³¹ ^99m
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 3: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in BPH patients on stable alpha-blocker therapy with tamsulosin 0.4 or 0.8 mg daily (Study 2)
	Vardenafil 10 mg Placebo-subtracted	Vardenafil 20 mg Placebo-subtracted
Standing SBP	-4 (-6.8, -0.3)	-4 (-6.8, -1.4)
Supine SBP	-5 (-8.2, -0.8)	-4 (-6.3, -1.8)

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
*Refer to for information regarding table. PRECAUTIONS, Drug Interactions
albuterol, systemic and inhaled	felodipinefinasteride	nizatidinenorfloxacin
amoxicillin	hydrocortisone	ofloxacin
ampicillin, with or without sulbactam	isoflurane isoniazid	omeprazole prednisone, prednisolone
atenolol	isradipine	ranitidine
azithromycin	influenza vaccine	rifabutin
caffeine, dietary ingestion	ketoconazo lelomefloxacin	roxithromycin sorbitol
cefaclor	mebendazole	(purgative doses do not
co-trimoxazole (trimethoprim and sulfamethoxazole)	medroxyprogesteronemethylprednisolone	inhibit theophylline absorption)
diltiazem	metronidazole	sucralfate
dirithromycin	metoprolol	terbutaline, systemic
enflurane	nadolol	terfenadine
famotidine	nifedipine	tetracycline
		tocainide

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Table 3: Clinically Significant drug interactions with Celecoxib
Drugs That Interfere with Hemostasis
Clinical Impact :	Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of Celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention :	Monitor patients with concomitant use of celecoxib capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact :	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200-400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100-325 mg).
Intervention :	Concomitant use of celecoxib capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Celecoxib capsules are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors , Angiotensin Receptor Blockers , and Beta - Blockers
Clinical Impact :	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention :	During concomitant use of celecoxib capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of celecoxib capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact :	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention :	During concomitant use of celecoxib capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact :	The concomitant use of Celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention :	During concomitant use of celecoxib capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact :	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention :	During concomitant use of celecoxib capsules and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact :	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Celecoxib has no effect on methotrexate pharmacokinetics.
Intervention :	During concomitant use of celecoxib capsules and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact :	Concomitant use of celecoxib capsules and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention :	During concomitant use of celecoxib capsules and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact :	Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention :	The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact :	Concomitant use of celecoxib capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention :	During concomitant use of celecoxib capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or inducers
Clinical Impact :	Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Coadministration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib.
Intervention :	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [see Clinical Pharmacology (12.3)].
CYP2D6 substrates
Clinical Impact :	In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs.
Intervention :	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [see Clinical Pharmacology (12.3)].
Corticosteroids
Clinical Impact :	Concomitant use of corticosteroids with celecoxib capsules may increase the risk of GI ulceration or bleeding.
Intervention :	Monitor patients with concomitant use of celecoxib capsules with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)].

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of this product. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Table 2. Drugs That May Decrease T4 Absorption (Hypothyroidism)
Potential impact: Concurrent use may reduce the efficacy of SYNTHROID by binding and delaying or preventing absorption, potentially resulting in hypothyroidism.
Drug or Drug Class	Effect
Calcium Carbonate Ferrous Sulfate	Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer SYNTHROID at least 4 hours apart from these agents.
Orlistat	Monitor patients treated concomitantly with orlistat and SYNTHROID for changes in thyroid function.
Bile Acid Sequestrants - Colesevelam - Cholestyramine - Colestipol Ion Exchange Resins - Kayexalate - Sevelamer	Bile acid sequestrants and ion exchange resins are known to decrease levothyroxine absorption. Administer SYNTHROID at least 4 hours prior to these drugs or monitor TSH levels.
Other drugs: Proton Pump Inhibitors Sucralfate Antacids - Aluminum & Magnesium Hydroxides - Simethicone	Gastric acidity is an essential requirement for adequate absorption of levothyroxine. Sucralfate, antacids and proton pump inhibitors may cause hypochlorhydria, affect intragastric pH, and reduce levothyroxine absorption. Monitor patients appropriately.

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Table 5. Food and Beverages to Avoid and Those which are Acceptable [see References (15)]
Class of Food and Beverage	Tyramine-Rich Foods and Beverages to Avoid	Acceptable Foods and Drinks, Containing No or Little Tyramine
Meat, Poultry, and Fish	Air dried, aged and fermented meats, sausages and salamis (including cacciatore, hard salami and mortadella); pickled herring; and any spoiled or improperly stored meat, poultry, and fish (e.g., foods that have undergone changes in coloration, odor, or become moldy); spoiled or improperly stored animal livers	Fresh meat, poultry, and fish, including fresh processed meats (e.g., lunch meats, hot dogs, breakfast sausage, and cooked sliced ham)
Vegetables	Broad bean pods (fava bean pods)	All other vegetables
Dairy	Aged cheeses	Processed cheeses, mozzarella, ricotta cheese, cottage cheese, and yogurt
Beverages	All varieties of tap beer and beers that have not been pasteurized so as to allow for ongoing fermentation	Concomitant use of alcohol with EMSAM is not recommended. (Bottled and canned beers and wines contain little or no tyramine.)
Miscellaneous	Concentrated yeast extract (e.g., Marmite), sauerkraut, most soybean products (including soy sauce and tofu), OTC supplements containing tyramine	Brewer’s yeast, baker’s yeast, soy milk, commercial chain restaurant pizzas prepared with cheeses low in tyramine

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Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.8)].

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AED Co-administered	AED Concentration	Topiramate Concentration
NC = Less than 10% change in plasma concentration. NE = Not Evaluated
Phenytoin	NC or 25% increase = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide = Is not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Table 8: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)]
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.9)].
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.11) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs [see Adverse Reactions (6.1)].
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution Two-fold increase in exposure	Monitor for sildenafil toxicity [see Clinical Pharmacology (12.3)].
Duloxetine	Avoid Use Five-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity.
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

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Drugs that Affect Renal Function	A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDs], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics	Dofetilide	Concomitant administration with digoxin was associated with a higher rate of torsades de pointes.
	Sotalol	Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
	Dronedarone	Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog	Teriparatide	Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement	Thyroid	Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics	Epinephrine Norepinephrine Dopamine	Can increase the risk of cardiac arrhythmias.
Neuromuscular Blocking Agents	Succinylcholine	May cause sudden extrusion of potassium from muscle cells, causing arrhythmias in patients taking digoxin.
Supplements	Calcium	If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers		Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.
Ivabradine	Can increase the risk of bradycardia.

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Table 13. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
* Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing.
	20 mg/day	4 mg/day	1.6	-	Do not exceed 8 mg/day
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed

Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Concomitant Drug Name or Drug Class	Clinical Rationale and Magnitude of Drug Interaction	Clinical Recommendation
Strong and moderate CYP3A4 inhibitors, e.g., ketoconazole, fluconazole	Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in an increase in exposure	Consider dose reduction [see Dosage and Administration ( 2.7 )]
Strong and moderate CYP3A4 inducers, e.g., rifampin, efavirenz	Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in a decrease in exposure	Consider dose increase [see Dosage and Administration ( 2.7 )]

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Table 1: Clinically Significant Drug Interactions with Naproxen
Drugs That Interfere with Hemostasis
Clinical Impact:	Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of naproxen tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	Concomitant use of naproxen tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding ( see WARNINGS; Hematologic Toxicity). Naproxen tablets are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of naproxen tablets and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of naproxen tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention	During concomitant use of naproxen tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of naproxen tablets and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen tablets and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen tablets and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen tablets and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen tablets and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen tablets and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of naproxen tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen tablets are not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen tablets are not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxen tablets are not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen tablets and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:	Patients simultaneously receiving naproxen tablets and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( 2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents	Carefully monitor blood glucose ( 5.11, 7.3)

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Table 2Clinically Significant Drug Interactions with Indomethacin Drugs That Interfere with Hemostasis
Clinical Impact:	Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant uses of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of indomethacin capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention:	Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Indomethacin capsules are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of indomethacin capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of Indomethacin capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. It has been reported that the addition of triamterene to a maintenance schedule of Indomethacin capsules resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin capsules and triamterene should not be administered together. Both Indomethacin capsules and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin capsules and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently.
Intervention:	Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact:	The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin. [see Clinical Pharmacology (12.3)]. In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage.
Intervention:	The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Probenecid
Clinical Impact:	When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased.
Intervention:	During the concomitant use of indomethacin capsules and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments.

Table name:

Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

Table name:

Table 2: Clinically Significant Drug Interactions with mefenamic acid
Drugs That Interfere with Hemostasis
Clinical Impact:	Mefenamic acid and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of mefenamic acid and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of PONSTEL with anticoagulants (e.g.,warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	Concomitant use of PONSTEL and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). PONSTEL is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of PONSTEL and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of PONSTEL and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention	During concomitant use of PONSTEL with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact:	The concomitant use of mefenamic acid with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of PONSTEL and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of PONSTEL and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of PONSTEL and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of PONSTEL and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention:	During concomitant use of PONSTEL and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of mefenamic acid with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	The concomitant use of mefenamic acid with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of PONSTEL and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of PONSTEL and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacid
Clinical Impact:	In a single dose study (n=6), ingestion of an antacid containing 1.7-gram of magnesium hydroxide with 500-mg of mefenamic acid increased the C_max and AUC of mefenamic acid by 125% and 36%, respectively.
Intervention:	Concomitant use of mefenamic acid and antacids is not generally recommended because of possible increased adverse events .

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin	Monitor phenytoin level (7)
Methotrexate	Monitor for methotrexate toxicity (7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)

Table name: Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations

Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference)		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	Cmax	Risperidone Dose Recommendation
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine concentrations approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine and carbamazepine epoxide	? carbamazepine epoxide	May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Table 13 Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
↓ = Decreased (induces lamotrigine glucuronidation) ↑ = Increased (inhibits lamotrigine glucuronidation) ? = Conflicting data
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine concentrations approximately 50%
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%
Carbamazepine and Carbamazepine epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%
	? Carbamazepine epoxide	May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold
	? valproate	There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations

Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

Table name:

Drugs That Interfere with Hemostasis
Clinical Impact:	Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of diclofenac sodium and misoprostol with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact:		Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention:		Concomitant use of diclofenac sodium and misoprostol and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Diclofenac sodium and misoprostol is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:		NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:		The concomitant administration of these drugs should be done with caution. Patients should be adequately hydrated and the clinical need to monitor the renal function should be assessed at the beginning of the concomitant treatment and periodically thereafter. During concomitant use of diclofenac sodium and misoprostol and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of diclofenac sodium and misoprostol and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)].
Diuretics
Clinical Impact:		Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:		During concomitant use of diclofenac sodium and misoprostol with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact:		The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:		During concomitant use of diclofenac sodium and misoprostol and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:		NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:		During concomitant use of diclofenac sodium and misoprostol and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:		Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:		During concomitant use of diclofenac sodium and misoprostol and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:		Concomitant use of diclofenac and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:		During concomitant use of diclofenac sodium and misoprostol and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:		Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention:		The concomitant use of diclofenac sodium and misoprostol with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:		Concomitant use of diclofenac and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:		During concomitant use of diclofenac sodium and misoprostol and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids
Clinical Impact:		Antacids reduce the bioavailability of misoprostol acid. Antacids may also delay absorption of diclofenac. Magnesium-containing antacids exacerbate misoprostol-associated diarrhea.
Intervention:		Concomitant use of diclofenac sodium and misoprostol and magnesium-containing antacids is not recommended.
Corticosteroids
Clinical Impact:		Concomitant use of corticosteroids with diclofenac may increase the risk of GI ulceration or bleeding.
Intervention		Monitor patients with concomitant use of diclofenac sodium and misoprostol with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)].
CYP2C9 Inhibitors or Inducers
Clinical Impact:		Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Co-administration of diclofenac with CYP2C9 inhibitors (e.g. voriconazole) may enhance the exposure and toxicity of diclofenac [see Clinical Pharmacology (12.3)] whereas co-administration with CYP2C9 inducers (e.g., rifampin) may lead to compromised efficacy of diclofenac.
Intervention:		CYP 2C9 inhibitors: When concomitant use of CYP2C9 inhibitors is necessary, the total daily dose of diclofenac should not exceed the lowest recommended dose of diclofenac sodium 50 mg and misoprostol 200 mcg twice daily [see Dosage and Administration (2)]. CYP2C9 inducers: A dosage adjustment may be warranted when diclofenac sodium and misoprostol is administered with CYP2C9 inducers. Administer the separate products of misoprostol and diclofenac if a higher dose of diclofenac is deemed necessary.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

Table name:

DRUG	DESCRIPTION OF INTERACTION
Heparin	Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin treated patients.
Pyrazinamide	Inhibits pyrazinamide-induced hyperuricemia.
Uricosuric Agents	Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including : antacids, sucralfate, multivitamins	Decreased moxifloxacin hydrochloride absorption. Take moxifloxacin hydrochloride at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time/INR, and bleeding. (6, 7.2, 12.3)
Class IA and Class III antiarrhythmics:	Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.3, 7.4)
Antidiabetic agents	Carefully monitor blood glucose. (5.10, 7.3)

•
Drugs That Interfere with Hemostasis
Clinical Impact:
Intervention:	Monitor patients with concomitant use of diclofenac sodium topical gel with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention:	Concomitant use of diclofenac sodium topical gel and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Diclofenac sodium topical gel is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:
Intervention:
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of diclofenac sodium topical gel with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact:	The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of diclofenac sodium topical gel and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of diclofenac sodium topical gel and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of diclofenac sodium topical gel and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of diclofenac sodium topical gel and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention:	During concomitant use of diclofenac sodium topical gel and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention:	The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of diclofenac sodium topical gel and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of diclofenac sodium topical gel and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and Gl toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( > 1 µg/kg/min); Glucocorticoids (hydrocortisone > 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T ₄ and T ₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT ₄. Continued administration results in a decrease in serum T ₄ and normal FT ₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T ₄ and T ₃ to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT ₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T ₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T ₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5’-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone > 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T ₄ to T ₃, leading to decreased T ₃ levels. However, serum T ₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T ₃ and T ₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T ₃ concentrations by 30% with minimal change in serum T ₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T ₃ and T ₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ⁹⁹mTc
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.

Table name: Clinical RecommendationStrong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin)Increase plasma naloxegol concentrations and may increase the risk of adverse reactions [see Clinical Pharmacology (12.3) ]. Use with strong CYP3A4 inhibitors is contraindicated [see Contraindications (4) ].Moderate CYP3A4 inhibitors (e.g., diltiazem, erythromycin, verapamil)Avoid use with moderate CYP3A4 inhibitors; if unavoidable, decrease the dosage of MOVANTIK to 12.5 mg once daily and monitor for adverse reactions [see Dosage and Administration (2.4) ].Weak CYP3A4 inhibitors (e.g., quinidine, cimetidine)Clinically significant increases in naloxegol concentrations are not expected. No dosage adjustments are necessary. Grapefruit or grapefruit juiceThe effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain preparation was used (e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when another preparation was used (e.g., low dose, single strength).Can increase plasma naloxegol concentrations. Avoid consumption of grapefruit or grapefruit juice during treatment with MOVANTIK [see Dosage and Administration (2.1) ].CYP3A4 InducersStrong CYP3A4 inducers (e.g., rifampin, carbamazepine, St. John’s Wort)Significantly decrease plasma naloxegol concentrations and may decrease the efficacy of MOVANTIK [see Clinical Pharmacology (12.3) ]. Use with strong CYP3A4 inducers is not recommended.Other opioid antagonistsPotential for additive effect of opioid receptor antagonism and increased risk of opioid withdrawal.Avoid use of MOVANTIKwith another opioid antagonist.

Table 2. Effects of Other Drugs on MOVANTIK
Concomitant Agent	Mechanism of Action
CYP3A4 Inhibitors
















Other Drug Interactions

Table name:

Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine (CBZ) and CBZ epoxide	? CBZ epoxide	May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
*Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	Cmax
Enzyme (CYP2D6) inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not Needed

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Drugs That Interfere with Hemostasis
Clinical Impact:	• Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	• During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( > 1 µg/kg/min); Glucocorticoids (hydrocortisone > 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T ₄ and T ₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT ₄. Continued administration results in a decrease in serum T ₄ and normal FT ₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T ₄ and T ₃ to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT ₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T ₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T ₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5’-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone > 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T ₄ to T ₃, leading to decreased T ₃ levels. However, serum T ₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T ₃ and T ₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T ₃ concentrations by 30% with minimal change in serum T ₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T ₃ and T ₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ⁹⁹mTc
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.

Table name:

Table 3: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [See Clinical Pharmacology (12.3)]
Concomitant Drug Class: Drug Name	Effect on Concentration of Etravirine or Concomitant Drug	Clinical Comment
↑ = increase, ↓ = decrease, ↔ = no change
HIV-Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
efavirenzThe interaction between INTELENCE^® and the drug was evaluated in a clinical study. All other drug interactions shown are predicted. nevirapine	↓ etravirine	Combining two NNRTIs has not been shown to be beneficial. Concomitant use of INTELENCE^® with efavirenz or nevirapine may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE^®. INTELENCE^® and other NNRTIs should not be co-administered.
delavirdine	↑ etravirine	Combining two NNRTIs has not been shown to be beneficial. INTELENCE^® and delavirdine should not be co-administered.
HIV-Antiviral Agents: Protease Inhibitors (PIs)
atazanavir (without ritonavir)	↓ atazanavir	Concomitant use of INTELENCE^® with atazanavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of atazanavir. INTELENCE^® should not be co-administered with atazanavir without low-dose ritonavir.
atazanavir/ritonavir	↓ atazanavir ↑ etravirine	Concomitant use of INTELENCE^® with atazanavir/ritonavir may cause a significant decrease in atazanavir C_min and loss of therapeutic effect of atazanavir. In addition, the mean systemic exposure (AUC) of etravirine after co-administration of INTELENCE^® with atazanavir/ritonavir is anticipated to be higher than the mean systemic exposure of etravirine observed in the Phase 3 trials after co-administration of INTELENCE^® and darunavir/ritonavir (as part of the background regimen). INTELENCE^® and atazanavir/ritonavir should not be co-administered.
darunavir/ritonavir	↓ etravirine	The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE^® was co-administered with darunavir/ritonavir. Because all subjects in the Phase 3 trials received darunavir/ritonavir as part of the background regimen and etravirine exposures from these trials were determined to be safe and effective, INTELENCE^® and darunavir/ritonavir can be co-administered without dose adjustments.
fosamprenavir (without ritonavir)	↑ amprenavir	Concomitant use of INTELENCE^® with fosamprenavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of amprenavir. INTELENCE^® should not be co-administered with fosamprenavir without low-dose ritonavir.
fosamprenavir/ritonavir	↑ amprenavir	Due to a significant increase in the systemic exposure of amprenavir, the appropriate doses of the combination of INTELENCE^® and fosamprenavir/ritonavir have not been established. INTELENCE^® and fosamprenavir/ritonavir should not be co-administered.
indinavir (without ritonavir)	↓ indinavir	Concomitant use of INTELENCE^® with indinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of indinavir. INTELENCE^® should not be co-administered with indinavir without low-dose ritonavir.
lopinavir/ritonavir	↓ etravirine	The mean systemic exposure (AUC) of etravirine was reduced after co-administration of INTELENCE^® with lopinavir/ritonavir (tablet). Because the reduction in the mean systemic exposures of etravirine in the presence of lopinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE^® and lopinavir/ritonavir can be co-administered without dose adjustments.
nelfinavir (without ritonavir)	↑ nelfinavir	Concomitant use of INTELENCE^® with nelfinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of nelfinavir. INTELENCE^® should not be co-administered with nelfinavir without low-dose ritonavir.
ritonavir	↓ etravirine	Concomitant use of INTELENCE^® with ritonavir 600 mg b.i.d. may cause a significant decrease in the plasma concentration of etravirine and loss of therapeutic effect of INTELENCE^®. INTELENCE^® and ritonavir 600 mg b.i.d. should not be co-administered.
saquinavir/ritonavir	↓ etravirine	The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE^® was co-administered with saquinavir/ritonavir. Because the reduction in the mean systemic exposures of etravirine in the presence of saquinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE^® and saquinavir/ritonavir can be co-administered without dose adjustments.
tipranavir/ritonavir	↓ etravirine	Concomitant use of INTELENCE^® with tipranavir/ritonavir may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE^®. INTELENCE^® and tipranavir/ritonavir should not be co-administered.
CCR5 Antagonists
maraviroc	↔ etravirine ↓ maraviroc	When INTELENCE^® is co-administered with maraviroc in the absence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 600 mg b.i.d. No dose adjustment of INTELENCE^® is needed.
maraviroc/darunavir/ritonavir The reference for etravirine exposure is the pharmacokinetic parameters of etravirine in the presence of darunavir/ritonavir	↔ etravirine ↑ maraviroc	When INTELENCE^® is co-administered with maraviroc in the presence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 150 mg b.i.d. No dose adjustment of INTELENCE^® is needed.
Other Agents
Antiarrhythmics: digoxin	↔ etravirine ↑ digoxin	For patients who are initiating a combination of INTELENCE^® and digoxin, the lowest dose of digoxin should initially be prescribed. For patients on a stable digoxin regimen and initiating INTELENCE^®, no dose adjustment of either INTELENCE^® or digoxin is needed. The serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.
amiodarone, bepridil, disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine	↓ antiarrhythmics	Concentrations of these antiarrhythmics may be decreased when co-administered with INTELENCE^®. INTELENCE^® and antiarrhythmics should be co-administered with caution. Drug concentration monitoring is recommended, if available.
Anticoagulants: warfarin	↑ anticoagulants	Warfarin concentrations may be increased when co-administered with INTELENCE^®. The international normalized ratio (INR) should be monitored when warfarin is combined with INTELENCE^®.
Anticonvulsants: carbamazepine, phenobarbital, phenytoin	↓ etravirine	Carbamazepine, phenobarbital and phenytoin are inducers of CYP450 enzymes. INTELENCE^® should not be used in combination with carbamazepine, phenobarbital, or phenytoin as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE^®.
Antifungals: fluconazole, voriconazole	↑ etravirine ↔ fluconazole ↑ voriconazole	Co-administration of etravirine and fluconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and fluconazole should be co-administered with caution. No dose adjustment of INTELENCE^® or fluconazole is needed.
		Co-administration of etravirine and voriconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and voriconazole should be co-administered with caution. No dose adjustment of INTELENCE^® or voriconazole is needed.
Antifungals: itraconazole, ketoconazole, posaconazole	↑ etravirine ↓ itraconazole ↓ ketoconazole ↔ posaconazole	Posaconazole, a potent inhibitor of CYP3A4, may increase plasma concentrations of etravirine. Itraconazole and ketoconazole are potent inhibitors as well as substrates of CYP3A4. Concomitant systemic use of itraconazole or ketoconazole and INTELENCE^® may increase plasma concentrations of etravirine. Simultaneously, plasma concentrations of itraconazole or ketoconazole may be decreased by INTELENCE^®. Dose adjustments for itraconazole, ketoconazole or posaconazole may be necessary depending on the other co-administered drugs.
Antiinfectives: clarithromycin	↑ etravirine ↓ clarithromycin ↑ 14-OH-clarithromycin	Clarithromycin exposure was decreased by INTELENCE^®; however, concentrations of the active metabolite, 14-hydroxy-clarithromycin, were increased. Because 14-hydroxy-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered for the treatment of MAC.
Antimycobacterials: rifampin, rifapentine	↓ etravirine	Rifampin and rifapentine are potent inducers of CYP450 enzymes. INTELENCE^® should not be used with rifampin or rifapentine as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE^®.
Antimycobacterials: rifabutin	↓ etravirine ↓ rifabutin ↓ 25-O-desacetylrifabutin	If INTELENCE^® is NOT co-administered with a protease inhibitor/ritonavir, then rifabutin at a dose of 300 mg q.d. is recommended. If INTELENCE^® is co-administered with darunavir/ritonavir, lopinavir/ritonavir or saquinavir/ritonavir, then rifabutin should not be co-administered due to the potential for significant reductions in etravirine exposure.
Benzodiazepines: diazepam	↑ diazepam	Concomitant use of INTELENCE^® with diazepam may increase plasma concentrations of diazepam. A decrease in diazepam dose may be needed.
Corticosteroids: dexamethasone (systemic)	↓ etravirine	Systemic dexamethasone induces CYP3A and can decrease etravirine plasma concentrations. This may result in loss of therapeutic effect of INTELENCE^®. Systemic dexamethasone should be used with caution or alternatives should be considered, particularly for long-term use.
Herbal Products: St. John's wort (Hypericum perforatum)	↓ etravirine	Concomitant use of INTELENCE^® with products containing St. John's wort may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE^®. INTELENCE^® and products containing St. John's wort should not be co-administered.
HMG-CoA Reductase Inhibitors: atorvastatin fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin	↔ etravirine ↓ atorvastatin ↑ 2-OH-atorvastatin ↔ etravirine ↑ fluvastatin, ↓ lovastatin, ↔ pravastatin, ↔ rosuvastatin, ↓ simvastatin	The combination of INTELENCE^® and atorvastatin can be given without dose adjustments, however, the dose of atorvastatin may need to be altered based on clinical response. No interaction between pravastatin, rosuvastatin and INTELENCE^® is expected. Lovastatin and simvastatin are CYP3A substrates and co-administration with INTELENCE^® may result in lower plasma concentrations of the HMG-CoA reductase inhibitor. Fluvastatin is metabolized by CYP2C9 and co-administration with INTELENCE^® may result in higher plasma concentrations of the HMG-CoA reductase inhibitor. Dose adjustments for these HMG-CoA reductase inhibitors may be necessary.
Immunosuppressants: cyclosporine, sirolimus, tacrolimus	↓ immunosuppressant	INTELENCE^® and systemic immunosuppressants should be co-administered with caution because plasma concentrations of cyclosporine, sirolimus, or tacrolimus may be affected.
Narcotic Analgesics: methadone	↔ etravirine ↔ methadone	INTELENCE^® and methadone can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as methadone maintenance therapy may need to be adjusted in some patients.
Phosphodiesterase Type 5 (PDE-5) Inhibitors: sildenafil, vardenafil, tadalafil	↓ sildenafil ↓ N-desmethyl-sildenafil	INTELENCE^® and sildenafil can be co-administered without dose adjustments, however, the dose of sildenafil may need to be altered based on clinical effect.
Platelet Aggregation Inhibitors: clopidogrel	↓ clopidogrel (active) metabolite	Activation of clopidogrel to its active metabolite may be decreased when clopidogrel is co-administered with INTELENCE^®. Alternatives to clopidogrel should be considered.

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Table 5. Clinically-Significant Drug Interactions with Sertraline Hydrochloride
Monoamine Oxidase Inhibitors ( MAOIs )
Clinical Impact :	The concomitant use of SSRIs including sertraline hydrochloride and MAOIs increases the risk of serotonin syndrome.
Intervention :	Sertraline hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [ See Dosage and Administration ( 2 . 5 ), Contraindications ( 4 ), Warnings and Precautions ( 5 . 2)].
Examples :	selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
Pimozide
Clinical Impact :	Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QT prolongation and ventricular arrhythmias.
Intervention :	Concomitant use of pimozide and sertraline hydrochloride is contraindicated [ See Contraindications ( 4)].
Other Serotonergic Drugs
Clinical Impact :	The concomitant use of serotonergic drugs with sertraline hydrochloride increases the risk of serotonin syndrome.
Intervention :	Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of sertraline hydrochloride and/or concomitant serotonergic drugs [ See Warnings and Precautions ( 5 . 2)].
Examples :	other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort
Drugs that Interfere with Hemostasis ( antiplatelet agents and anticoagulants )
Clinical Impact :	The concurrent use of an antiplatelet agent or anticoagulant with sertraline hydrochloride may potentiate the risk of bleeding.
Intervention :	Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [ See Warnings and Precautions ( 5 . 3)].
Examples :	aspirin, clopidogrel, heparin, warfarin
Drugs Highly Bound to Plasma Protein
Clinical Impact :	Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of sertraline hydrochloride with another drug that is highly bound to plasma protein may increase free concentrations of sertraline hydrochloride or other tightly-bound drugs in plasma [ See Clinical Pharmacology ( 12 . 3 )].
Intervention :	Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs as warranted.
Examples :	warfarin
Drugs Metabolized by CYP2D6
Clinical Impact :	Sertraline hydrochloride is a CYP2D6 inhibitor [ See Clinical Pharmacology ( 12 . 3)]. The concomitant use of sertraline hydrochloride with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate.
Intervention :	Decrease the dosage of a CYP2D6 substrate if needed with concomitant sertraline hydrochloride use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride is discontinued.
Examples :	propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine
Phenytoin
Clinical Impact :	Phenytoin is a narrow therapeutic index drug. Sertraline hydrochloride may increase phenytoin concentrations.
Intervention :	Monitor phenytoin levels when initiating or titrating sertraline hydrochloride. Reduce phenytoin dosage if needed.
Examples :	phenytoin, fosphenytoin

Table name:

Factors	Dosage Adjustments for Aripirazole Tablets
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors	Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double usual dose over 1 to 2 weeks

Table 3: Clinically Relevant Interactions Affecting Drugs Co-Administered with Omeprazole and Interaction with Diagnostics
Antiretrovirals
Clinical Impact:	The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
Intervention:	Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications (4)]. Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:	Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention:	Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact:	Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].
Intervention:	A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact:	Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)]. There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention:	Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6)].
Citalopram
Clinical Impact:	Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention:	Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:	Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].
Intervention:	Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:	Potential for increased exposure of phenytoin.
Intervention:	Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:	Increased exposure of diazepam [see Clinical Pharmacology (12.3)].
Intervention:	Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:	Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention:	Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:	Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:	Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)]. See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:	Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:	See Contraindications, Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact:	Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention:	Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:	Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10), Clinical Pharmacology (12.2)].
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:	Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact:	There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:	An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:	There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:	Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.

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Table 2: Clinically Significant Drug Interactions with Opana
Alcohol
Clinical Impact:	The concomitant use of alcohol with OPANA can result in an increase of oxymorphone plasma levels and potentially fatal overdose of oxymorphone.
Intervention:	Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while on OPANA therapy [see Clinical Pharmacology (12.3)].
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines and other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [ Warnings and Precautions (5.4)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue OPANA if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)]. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Intervention:	The use of OPANA is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of OPANA and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine,
Muscle Relaxants
Clinical Impact:	Oxymorphone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of OPANA and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when OPANA is used concomitantly with anticholinergic drugs.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when OPANA is used concomitantly with anticholinergic drugs.
Cimetidine
Clinical Impact:	Cimetidine can potentiate opioid-induced respiratory depression.
Intervention:	Monitor patients for respiratory depression when OPANA and cimetidine are used concurrently.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Amiodarone, verapamil, diltiazem	Do not exceed 10 mg simvastatin daily
Amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Table 7: Selected Drug Interactions in Adults
Concomitant Drug Class: Drug Name	Effect on Concentration of Raltegravir	Clinical Comment
HIV-1-Antiviral Agents
atazanavir	↑	Atazanavir, a strong inhibitor of UGT1A1, increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
atazanavir/ritonavir	↑	Atazanavir/ritonavir increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
efavirenz	↓	Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
etravirine	↓	Etravirine reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
tipranavir/ritonavir	↓	Tipranavir/ritonavir reduces plasma concentrations of raltegravir. However, since comparable efficacy was observed for this combination relative to other ISENTRESS-containing regimens in Phase 3 studies 018 and 019, no dose adjustment is recommended.
Other Agents
omeprazole	↑	Coadministration of medicinal products that increase gastric pH (e.g., omeprazole) may increase raltegravir levels based on increased raltegravir solubility at higher pH. However, since concomitant use of ISENTRESS with proton pump inhibitors and H2 blockers did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
rifampin	↓	Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of raltegravir. The recommended dosage of ISENTRESS is 800 mg twice daily during coadministration with rifampin.

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
* The interaction between immediate-release VIRAMUNE and the drug was evaluated in a clinical study. The results of drug interaction studies with immediate-release VIRAMUNE are expected to also apply to VIRAMUNE XR.
Drug Name	Effect on Concentration of Nevirapine or Concomitant Drug	Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir*	↓ Atazanavir ↑ Nevirapine	Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir*	↓ Amprenavir ↑ Nevirapine	Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir*	↓ Amprenavir ↑ Nevirapine	No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir*	↓ Indinavir	The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir*	↓Lopinavir	Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra^® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir*	↓Nelfinavir M8 Metabolite ↓Nelfinavir C_min	The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/ritonavir	The interaction between nevirapine and saquinavir/ritonavir has not been evaluated	The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz*	↓ Efavirenz	The appropriate doses of these combinations with respect to safety and efficacy have not been established.
Delavirdine Etravirine Rilpivirine		Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.
Hepatitis C Antiviral Agents
Boceprevir	Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine.	Nevirapine and boceprevir should not be coadministered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy.
Telaprevir	Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir.	Nevirapine and telaprevir should not be coadministered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events.
Other Agents
Analgesics:
Methadone*	↓ Methadone	Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics:
Amiodarone, disopyramide, lidocaine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Antibiotics:
Clarithromycin*	↓ Clarithromycin ↑ 14-OH clarithromycin	Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Rifabutin*	↑ Rifabutin	Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin*	↓ Nevirapine	Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants: Carbamazepine, clonazepam, ethosuximide	Plasma concentrations of nevirapine and the anticonvulsant may be decreased.	Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals:
Fluconazole*	↑Nevirapine	Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Ketoconazole*	↓ Ketoconazole	Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Itraconazole	↓ Itraconazole	Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics: Warfarin	Plasma concentrations may be increased.	Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers: Diltiazem, nifedipine, verapamil	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Cancer chemotherapy: Cyclophosphamide	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Ergot alkaloids: Ergotamine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Motility agents: Cisapride	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Opiate agonists: Fentanyl	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Oral contraceptives:
Ethinyl estradiol and Norethindrone*	↓ Ethinyl estradiol ↓ Norethindrone	Despite lower ethinyl estradiol and norethindrone exposures when coadministered with nevirapine, literature reports suggest that nevirapine has no effect on pregnancy rates among HIV-infected women on combined oral contraceptives. When coadministered with VIRAMUNE XR, no dose adjustment of ethinyl estradiol or norethindrone is needed when used in combination for contraception When oral contraceptives are used for hormonal regulation during VIRAMUNE XR therapy, the therapeutic effect of the hormonal therapy should be monitored.

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Bleeding times
Clinical Impact:	Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention:	This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact:	The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention:	Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact:	Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention:	This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.

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Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Drugs/Dietary Supplements That Decrease Cyclosporine Concentrations
Antibiotics nafcillin rifampin	Anticonvulsants carbamazepine oxcarbazepine phenobarbital phenytoin	Other Drugs / Dietary Supplements bosentan octreotide orlistat St. John’s Wort sulfinpyrazone terbinafine ticlopidine

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

Table name: Clinical ImpactSignificantly increased exposure of aprepitant may increase the risk of adverse reactions associated with aprepitant [see ADVERSE REACTIONS (6.1) and CLINICAL PHARMACOLOGY (12.3)].InterventionAvoid concomitant use of aprepitantExamplesModerate inhibitor: diltiazem Strong inhibitors: ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavirStrong CYP3A4 InducersClinical ImpactSubstantially decreased exposure of aprepitant in patients chronically taking a strong CYP3A4 inducer may decrease the efficacy of aprepitant [see CLINICAL PHARMACOLOGY (12.3)].InterventionAvoid concomitant use of aprepitantExamplesrifampin, carbamazepine, phenytoin


Moderate to Strong CYP3A4 Inhibitors

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Factors	Dosage Adjustments for Aripiprazole
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
Known CYP2D6 Poor Metabolizersand strong CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors	Administer half of usual dose
Strong CYP2D6 and CYP3A4inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double usual dose over 1 to 2 weeks

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitors (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 18. Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9- Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Co-administered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone) (RatioChange relative to reference)		Risperidone Dose Recommendation
	Co-administered Drug	Risperidone	AUC	C_max	Risperidone Dose Recommendation
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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a = Plasma concenrtration increased 25% in some patients, generally those on a twice a day dosing regimen
of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase ^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide ^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Table 4 Established and Other Potentially SignificantThis table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class: Drug Name	Effect on ConcentrationIncrease=↑; Decrease=↓; No Effect=↔	Clinical Comment
Antacids: antacids (e.g., aluminium, magnesium hydroxide, or calcium carbonate)	↔ rilpivirine (antacids taken at least 2 hours before or at least 4 hours after rilpivirine) ↓ rilpivirine (concomitant intake)	The combination of COMPLERA and antacids should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). Antacids should only be administered either at least 2 hours before or at least 4 hours after COMPLERA.
Antimycobacterials: rifabutin	↓ rilpivirineThe interaction was evaluated in a clinical study. All other drug-drug interactions shown are predicted.	Concomitant use of COMPLERA with rifabutin may cause significant decreases in rilpivirine plasma concentrations (induction of CYP3A enzymes). If COMPLERA is coadministered with rifabutin, an additional 25 mg tablet of rilpivirine (Edurant) once per day is recommended to be taken concomitantly with COMPLERA and with a meal for the duration of rifabutin coadministration.
Azole Antifungal Agents: fluconazole itraconazole ketoconazole posaconazole voriconazole	↑ rilpivirine ^, This interaction study has been performed with a dose higher than the recommended dose for rilpivirine. The dosing recommendation is applicable to the recommended dose of rilpivirine 25 mg once daily. ↓ ketoconazole ^,	Concomitant use of COMPLERA with azole antifungal agents may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when COMPLERA is coadministered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are coadministered with COMPLERA.
Hepatitis C Antiviral Agents: ledipasvir/sofosbuvir	↑ tenofovir	Patients receiving COMPLERA concomitantly with HARVONI™ (ledipasvir/sofosbuvir) should be monitored for adverse reactions associated with tenofovir disoproxil fumarate.
H₂-Receptor Antagonists: cimetidine famotidine nizatidine ranitidine	↔ rilpivirine ^, (famotidine taken 12 hours before rilpivirine or 4 hours after rilpivirine) ↓ rilpivirine ^, (famotidine taken 2 hours before rilpivirine)	The combination of COMPLERA and H₂-receptor antagonists should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). H₂-receptor antagonists should only be administered at least 12 hours before or at least 4 hours after COMPLERA.
Macrolide or Ketolide Antibiotics: clarithromycin erythromycin telithromycin	↑ rilpivirine ↔ clarithromycin ↔ erythromycin ↔ telithromycin	Concomitant use of COMPLERA with clarithromycin, erythromycin, or telithromycin may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Where possible, alternatives such as azithromycin should be considered.
Narcotic Analgesics: methadone	↓ R(–) methadone ↓ S(+) methadone ↔ rilpivirine ↔ methadone (when used with tenofovir)	No dose adjustments are required when initiating coadministration of methadone with COMPLERA. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients.

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Interacting Drug	Interaction
Antacids, sucralfate, multivitamins, and other products containing multivalent cations	Moxifloxacin absorption is decreased. Administer AVELOX Tablet at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3, 17.2)
Warfarin	Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. (6.4, 7.2, 12.3)
Class IA and Class III antiarrhythmics:	Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.3, 7.4)

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Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Drug		Effect
Phenylephrine with prior administration of monoamine oxidase inhibitors (MAOI).		Cardiac pressor response potentiated. May cause acute hypertensive crisis.
Phenylephrine with tricyclic anti-depressants.		Pressor response increased.
Phenylephrine with ergot alkaloids.		Excessive rise in blood pressure.
Phenylephrine with bronchodilator sympathomimetic agents and with epinephrine or other sympathomimetics.		Tachycardia or other arrhythmias may occur.
Phenylephrine with prior administration of propranolol or other β-adrenergic blockers.		Cardiostimulating effects blocked.
Phenylephrine with atropine sulfate.		Reflex bradycardia blocked; pressor response enhanced.
Phenylephrine with prior administration of phentolamine or other α-adrenergic blockers.		Pressor response decreased.
Phenylephrine with diet preparations, such as amphetamines or phenylpropanolamine.		Synergistic adrenergic response.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.12, 7.3)

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Table 7: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class: Drug Name	Effect	Clinical Comment
^* The interaction between SUSTIVA and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.
This table is not all-inclusive.
HIV antiviral agents
Protease inhibitor: Fosamprenavir calcium	↓ amprenavir	Fosamprenavir (unboosted): Appropriate doses of the combinations with respect to safety and efficacy have not been established. Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when SUSTIVA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when SUSTIVA is administered with fosamprenavir plus ritonavir twice daily.
Protease inhibitor: Atazanavir sulfate	↓ atazanavir^*	Treatment-naive patients: When coadministered with SUSTIVA, the recommended dose of atazanavir is 400 mg with ritonavir 100 mg (together once daily with food) and SUSTIVA 600 mg (once daily on an empty stomach, preferably at bedtime). Treatment-experienced patients: Coadministration of SUSTIVA and atazanavir is not recommended.
Protease inhibitor: Indinavir	↓ indinavir^*	The optimal dose of indinavir, when given in combination with SUSTIVA, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to SUSTIVA. When indinavir at an increased dose (1000 mg every 8 hours) was given with SUSTIVA (600 mg once daily), the indinavir AUC and C_min were decreased on average by 33-46% and 39-57%, respectively, compared to when indinavir (800 mg every 8 hours) was given alone.
Protease inhibitor: Lopinavir/ritonavir	↓ lopinavir^*	Lopinavir/ritonavir tablets should not be administered once daily in combination with SUSTIVA. In antiretroviral-naive patients, lopinavir/ritonavir tablets can be used twice daily in combination with SUSTIVA with no dose adjustment. A dose increase of lopinavir/ritonavir tablets to 600/150 mg (3 tablets) twice daily may be considered when used in combination with SUSTIVA in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). A dose increase of lopinavir/ritonavir oral solution to 533/133 mg (6.5 mL) twice daily taken with food is recommended when used in combination with SUSTIVA.
Protease inhibitor: Ritonavir	↑ ritonavir^* ↑ efavirenz^*	When ritonavir 500 mg q12h was coadministered with SUSTIVA 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (eg, dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when SUSTIVA is used in combination with ritonavir.
Protease inhibitor: Saquinavir	↓ saquinavir^*	Should not be used as sole protease inhibitor in combination with SUSTIVA.
NNRTI: Other NNRTIs	↑ or ↓ efavirenz and/or NNRTI	Combining two NNRTIs has not been shown to be beneficial. SUSTIVA should not be coadministered with other NNRTIs.
CCR5 co-receptor antagonist: Maraviroc	↓ maraviroc^*	Refer to the full prescribing information for maraviroc for guidance on coadministration with efavirenz.
Integrase strand transfer inhibitor: Raltegravir	↓ raltegravir^*	SUSTIVA reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
Hepatitis C antiviral agents
Protease inhibitor: Boceprevir	↓ boceprevir^*	Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with SUSTIVA, which may result in loss of therapeutic effect. The combination should be avoided.
Protease inhibitor: Telaprevir	↓ telaprevir^* ↓ efavirenz^*	Concomitant administration of telaprevir and SUSTIVA resulted in reduced steady-state exposures to telaprevir and efavirenz.
Other agents
Anticoagulant: Warfarin	↑ or ↓ warfarin	Plasma concentrations and effects potentially increased or decreased by SUSTIVA.
Anticonvulsants: Carbamazepine	↓ carbamazepine^* ↓ efavirenz^*	There are insufficient data to make a dose recommendation for efavirenz. Alternative anticonvulsant treatment should be used.
Phenytoin Phenobarbital	↓ anticonvulsant ↓ efavirenz	Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
Antidepressants: Bupropion	↓ bupropion^*	The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded.
Sertraline	↓ sertraline^*	Increases in sertraline dosage should be guided by clinical response.
Antifungals: Voriconazole	↓ voriconazole^* ↑ efavirenz^*	SUSTIVA and voriconazole must not be coadministered at standard doses. Efavirenz significantly decreases voriconazole plasma concentrations, and coadministration may decrease the therapeutic effectiveness of voriconazole. Also, voriconazole significantly increases efavirenz plasma concentrations, which may increase the risk of SUSTIVA-associated side effects. When voriconazole is coadministered with SUSTIVA, voriconazole maintenance dose should be increased to 400 mg every 12 hours and SUSTIVA dose should be decreased to 300 mg once daily using the capsule formulation. SUSTIVA tablets should not be broken. [See Dosage and Administration (2.1) and Clinical Pharmacology (12.3, Tables 8 and 9) .]
Itraconazole	↓ itraconazole^* ↓ hydroxyitraconazole^*	Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
Ketoconazole	↓ ketoconazole	Drug interaction studies with SUSTIVA and ketoconazole have not been conducted. SUSTIVA has the potential to decrease plasma concentrations of ketoconazole.
Posaconazole	↓ posaconazole^*	Avoid concomitant use unless the benefit outweighs the risks.
Anti-infective: Clarithromycin	↓ clarithromycin^* ↑ 14-OH metabolite^*	Plasma concentrations decreased by SUSTIVA; clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving SUSTIVA and clarithromycin. No dose adjustment of SUSTIVA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered (see Other Drugs , following table). Other macrolide antibiotics, such as erythromycin, have not been studied in combination with SUSTIVA.
Antimycobacterials: Rifabutin	↓ rifabutin^*	Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
Rifampin	↓ efavirenz^*	If SUSTIVA is coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of SUSTIVA to 800 mg once daily is recommended.
Calcium channel blockers: Diltiazem	↓ diltiazem^* ↓ desacetyl diltiazem^* ↓ N-monodesmethyl diltiazem^*	Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of efavirenz is necessary when administered with diltiazem.
Others (eg, felodipine, nicardipine, nifedipine, verapamil)	↓ calcium channel blocker	No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker).
HMG-CoA reductase inhibitors: Atorvastatin Pravastatin Simvastatin	↓ atorvastatin^* ↓ pravastatin^* ↓ simvastatin^*	Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
Hormonal contraceptives: Oral Ethinyl estradiol/ Norgestimate	↓ active metabolites of norgestimate^*	A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed.
Implant Etonogestrel	↓ etonogestrel	A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A	↓ immunosuppressant	Decreased exposure of the immunosuppressant may be expected due to CYP3A induction. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with efavirenz.
Narcotic analgesic: Methadone	↓ methadone^*	Coadministration in HIV-infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.

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Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table 2. Effects of Other Drugs on MOVANTIK
Concomitant Agent	Mechanism of Action
CYP3A4 Inhibitors
















Other Drug Interactions

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Drugs That Interfere with Hemostasis
Clinical Impact:	• Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	• During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

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Name of the Concomitant Drug	Change in the Concentration of Ganciclovir or Concomitant Drug	Clinical Comment
Zidovudine	↓ Ganciclovir ↑ Zidovudine	Zidovudine and valganciclovir hydrochloride each have the potential to cause neutropenia and anemia
Probenecid	↑ Ganciclovir	Patients taking probenecid and valganciclovir hydrochloride should be monitored for evidence of ganciclovir toxicity
Mycophenolate Mofetil (MMF)	↔ Ganciclovir (in patients with normal renal function) ↔ MMF (in patients with normal renal function)	Patients with renal impairment should be monitored carefully as levels of MMF metabolites and ganciclovir may increase
Didanosine	↓ Ganciclovir ↑ Didanosine	Patients should be closely monitored for didanosine toxicity

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Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.6).]
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported . Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [see Adverse Reactions (6.1).]
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution 2-fold increase in exposure	Monitor for sildenafil toxicity (see Pharmacokinetics -(12.3)-] .
Duloxetine	Avoid Use 5-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx ^® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2)].	Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

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Table 2 Rifabutin Interaction Studies
Coadministered drug	Dosing regimen of coadministered drug	Dosing regimen of rifabutin	Study population (n)	Effect on rifabutin	Effect on coadministered drug	Recommendation
↑ indicates increase; ↓ indicates decrease; ↔ indicates no significant change QD- once daily; BID- twice daily; TID – thrice daily ND - No Data AUC - Area under the Concentration vs. Time Curve; C _max - Maximum serum concentration
ANTIVIRALS
Amprenavir	1200 mg BID × 10 days	300 mg QD × 10 days	Healthy male subjects (6)	↑ AUC by 193%, ↑ Cmax by 119%	↔	Reduce rifabutin dose by at least 50%. Monitor closely for adverse reactions.
Delavirdine	400 mg TID	300 mg QD	HIV-infected patients (7)	↑ AUC by 230%, ↑ Cmax by 128%	↓ AUC by 80%, ↓ Cmax by 75%, ↓ Cmin by 17%	CONTRAINDICATED
Didanosine	167 or 250 mg BID × 12 days	300 or 600 mg QD × 1	HIV-infected patients (11)	↔	↔
Fosamprenavir/ ritonavir	700 mg BID plus ritonavir 100 mg BID × 2 weeks	150 mg every other day × 2 weeks	Healthy subjects (15)	↔ AUC compared to rifabutin 300 mg QD alone ↓ Cmax by 15%	↑ AUC by 35% compared to historical control (fosamprenavir/ritonavir 700/100 mg BID), ↑ Cmax by 36%, ↑ Cmin by 36%,	Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with fosamprenavir/ritonavir combination.
Indinavir	800 mg TID × 10 days	300 mg QD × 10 days	Healthy subjects (10)	↑ AUC by 173%, ↑ Cmax by 134%	↓ AUC by 34%, ↓ Cmax by 25%, ↓ Cmin by 39%	Reduce rifabutin dose by 50%, and increase indinavir dose from 800 mg to 1000 mg TID.
Lopinavir/ ritonavir	400/100 mg BID × 20 days	150 mg QD × 10 days	Healthy subjects (14)	↑ AUC by 203% also taking zidovudine 500 mg QD ↓ Cmax by 112%	↔	Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed.
Saquinavir/ ritonavir	1000/100 mg BID × 14 or 22 days	150 mg every 3 days × 21–22 days	Healthy subjects	↑ AUC by 53% compared to rifabutin 150 mg QD alone ↑ Cmax by 88% (n=11)	↓ AUC by 13%, ↓ Cmax by 15%, (n=19)	Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with saquinavir/ritonavir combination. Monitor closely for adverse reactions.
Ritonavir	500mg BID × 10 days	150 mg QD × 16 days	Healthy subjects (5)	↑ AUC by 300%, ↑ Cmax by 150%	ND	Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed.
Tipranavir/ ritonavir	500/200 BID × 15 doses	150 mg single dose	Healthy subjects (20)	↑ AUC by 190%, ↑ Cmax by 70%	↔	Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with tipranavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed.
Nelfinavir	1250 mg BID × 7–8 days	150 mg QD × 8 days	HIV-infected patients (11)	↑ AUC by 83%, compared to rifabutin 300 mg QD alone ↑ Cmax by 19%	↔	Reduce rifabutin dose by 50% (to 150 mg QD) and increase the nelfinavir dose to 1250 mg BID
Zidovudine	100 or 200 mg q4h	300 or 450 mg QD	HIV-infected patients (16)	↔	↓ AUC by 32%, ↓ Cmax by 48%,	Because zidovudine levels remained within the therapeutic range during coadministration of rifabutin, dosage adjustments are not necessary.
ANTIFUNGALS
Fluconazole	200 mg QD × 2 weeks	300 mg QD × 2 weeks	HIV-infected patients (12)	↑ AUC by 82%, ↑ Cmax by 88%	↔	Monitor for rifabutin associated adverse events. Reduce rifabutin dose or suspend MYCOBUTIN use if toxicity is suspected.
Posaconazole	200 mg QD × 10 days	300 mg QD × 17 days	Healthy subjects (8)	↑ AUC by 72%, ↑ Cmax by 31%	↓ AUC by 49%, ↓ Cmax by 43%	If co-administration of these two drugs cannot be avoided, patients should be monitored for adverse events associated with rifabutin administration, and lack of posaconazole efficacy.
Itraconazole	200 mg QD	300 mg QD	HIV-Infected patients (6)	↑ data from a case report	↓ AUC by 70%, ↓ Cmax by 75%,	If co-administration of these two drugs cannot be avoided, patients should be monitored for adverse events associated with rifabutin administration, and lack of itraconazole efficacy. In a separate study, one case of uveitis was associated with increased serum rifabutin levels following co-administration of rifabutin (300 mg QD) with itraconazole (600–900 mg QD).
Voriconazole	400 mg BID × 7 days (maintenance dose)	300 mg QD × 7 days	Healthy male subjects (12)	↑ AUC by 331%, ↑ Cmax by 195%	↑ AUC by ~100%, ↑ Cmax by ~100% compared to voriconazole 200 mg BID alone	CONTRAINDICATED
ANTI-PCP (Pneumocystis carinii pneumonia)
Dapsone	50 mg QD	300 mg QD	HIV-infected patients (16)	ND	↓ AUC by 27 –40%
Sulfamethoxazole- Trimethoprim	800/160 mg	300 mg QD	HIV-infected patients (12)	↔	↓ AUC by 15–20%
ANTI-MAC (Mycobacterium avium intracellulare complex)
Azithromycin	500 mg QD × 1 day, then 250 mg QD × 9 days	300 mg QD	Healthy subjects (6)	↔	↔
Clarithromycin	500 mg BID	300 mg QD	HIV-infected patients (12)	↑ AUC by 75%	↓ AUC by 50%	Monitor for rifabutin associated adverse events. Reduce dose or suspend use of MYCOBUTIN if toxicity is suspected. Alternative treatment for clarithromycin should be considered when treating patients receiving rifabutin
ANTI-TB (Tuberculosis)
Ethambutol	1200 mg	300 mg QD × 7 days	Healthy subjects (10)	ND	↔
Isoniazid	300 mg	300 mg QD × 7 days	Healthy subjects (6)	ND	↔
OTHER
Methadone	20 – 100 mg QD	300 mg QD × 13 days	HIV-infected patients (24)	ND	↔
Ethinylestradiol (EE)/Norethindrone (NE)	35 mg EE / 1 mg NE × 21 days	300 mg QD × 10 days	Healthy female subjects (22)	ND	EE: ↓ AUC by 35%, ↓ C _max by 20% NE: ↓ AUC by 46%	Patients should be advised to use additional or alternative methods of contraception.
Theophylline	5 mg/kg	300 mg × 14 days	Healthy subjects (11)	ND	↔

Table name:

Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( 7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( 7)
Phenytoin	Monitor phenytoin level ( 7)
Methotrexate	Monitor for methotrexate toxicity ( 7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine ( 7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin ( 7)

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Table 3Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

Table name:

Drug	Type of Interaction	Effect**
Adenosine	Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.
Alcohol	A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours.	30% increase
Allopurinol	Decreases theophylline clearance at allopurinol doses ≥600 mg/day.	25% increase
Aminoglutethimide	Increases theophylline clearance by induction of microsomal enzyme activity.	25% decrease
Carbamazepine	Similar to aminoglutethimide.	30% decrease
Cimetidine	Decreases theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase
Ciprofloxacin	Similar to cimetidine.	40% increase
Clarithromycin	Similar to erythromycin.	25% increase
Diazepam	Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.	Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram	Decreases theophylline clearance by inhibiting hydroxylation and demethylation.	50% increase
Enoxacin	Similar to cimetidine.	300% increase
Ephedrine	Synergistic CNS effects.	Increased frequency of nausea, nervousness, and insomnia.
Erythromycin	Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen	Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.	30% increase
Flurazepam	Similar to diazepam.	Similar to diazepam.
Fluvoxamine	Similar to cimetidine.	Similar to cimetidine.
Halothane	Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.	Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A	Decreases theophylline clearance.	100% increase
Isoproterenol (IV)	Increases theophylline clearance.	20% decrease
Ketamine	Pharmacologic.	May lower theophylline seizure threshold
Lithium	Theophylline increases renal lithium clearance.	Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam	Similar to diazepam.	Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.	20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine	Similar to disulfiram.	80% increase
Midazolam	Similar to diazepam.	Similar to diazepam.
Moricizine	Increases theophylline clearance.	25% decrease
Pancuronium	Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.	Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline	Decreases theophylline clearance.	30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.	25% decrease after two weeks of concurrent PB.
Phenytoin	Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.	Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone	Decreases theophylline clearance and pharmacologic interaction.	40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and pharmacologic interaction.	100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin	Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.	20-40% decrease
St. John’sWort (Hypericum Perforatum)	Decrease in theophylline plasma concentrations.	Higher doses of theophylline may be required to achieve desired effect. Stopping St. John’s Wort may result in theophylline toxicity.
Sulfinpyrazone	Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.	20% decrease
Tacrine	Similar to cimetidine, also increases renal clearance of theophylline.	90% increase
Thiabendazole	Decreases theophylline clearance.	190% increase
Ticlopidine	Decreases theophylline clearance.	60% increase
Troleandomycin	Similar to erythromycin.	33-100% increase depending on troleandomycin dose.
Verapamil	Similar to disulfiram.	20% increase

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Drugs That Interfere with Hemostasis
Clinical Impact:	· Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of Celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. · Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of celecoxib capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200-400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100-325 mg).
Intervention:	Concomitant use of celecoxib capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Celecoxib capsules are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	· NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). · In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	· During concomitant use of celecoxib capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. · During concomitant use of celecoxib capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. · When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of celecoxib capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact:	The concomitant use of Celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of celecoxib capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of celecoxib capsules and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). celecoxib capsules has no effect on methotrexate pharmacokinetics.
Intervention:	During concomitant use of celecoxib capsules and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of celecoxib capsules and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of celecoxib capsules and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention:	The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of celecoxib capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of celecoxib capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or inducers
Clinical Impact:	Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Coadministration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib.
Intervention	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [see Clinical Pharmacology ( 12.3)].
CYP2D6 substrates
Clinical Impact:	In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs.
Intervention	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [see Clinical Pharmacology ( 12.3)].
Corticosteroids
Clinical Impact:	Concomitant use of corticosteroids with celecoxib capsules may increase the risk of GI ulceration or bleeding.
Intervention	Monitor patients with concomitant use of celecoxib capsules with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)].

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TABLE 1. Clinically Significant Drug Interactions with DILAUDID INJECTION and/or DILAUDID-HP INJECTION
Benzodiazepines and other Central Nervous System Depressants (CNS)
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines and other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.3)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue DILAUDID INJECTION and DILAUDID-HP INJECTION if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.3)]. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Intervention:	The use of DILAUDID INJECTION or DILAUDID-HP INJECTION is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of DILAUDID INJECTION and DILAUDID-HP INJECTION and/or precipitate withdrawal syndrome.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine,
Muscle Relaxants
Clinical Impact:	Hydromorphone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of DILAUDID INJECTION and DILAUDID-HP INJECTION and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when DILAUDID INJECTION and DILAUDID-HP INJECTION are used concomitantly with anticholinergic drugs.

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

Table name:

Interacting Drug	Interaction
Drugs known to prolong QT interval (e.g., Class IA and Class III anti-arrhythmic agents).	Quinine Sulfate Capsules prolong QT interval, ECG abnormalities including QT prolongation and Torsades de Pointes. Avoid concomitant use (5.3).
Other antimalarials (e.g., halofantrine, mefloquine).	ECG abnormalities including QT prolongation. Avoid concomitant use (5.3, 7.2).
CYP3A4 inducers or inhibitors	Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine (7.1).
CYP3A4 and CYP2D6 substrates	Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the co-administered drug (7.2).
Digoxin	Increased digoxin plasma concentration (5.8, 7.1).

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Interacting Agent	Examples
Drugs that may increase phenytoin serum levels
Antiepileptic drugs	Ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate
Azoles	Fluconazole, ketoconazole, itraconazole, miconazole, voriconazole
Antineoplastic agents	Capecitabine, fluorouracil
Antidepressants	Fluoxetine, fluvoxamine, sertraline
Gastric acid reducing agents	H₂ antagonists (cimetidine), omeprazole
Sulfonamides	Sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole trimethoprim
Other	Acute alcohol intake, amiodarone, chloramphenicol, chlordiazepoxide, disulfiram, estrogen, fluvastatin, isoniazid, methylphenidate, phenothiazines, salicylates, ticlopidine, tolbutamide, trazodone, warfarin
Drugs that may decrease phenytoin serum levels
Antineoplastic agents usually in combination	Bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate
Antiviral agents	Fosamprenavir, nelfinavir, ritonavir
Antiepileptic drugs	Carbamazepine, vigabatrin
Other	Chronic alcohol abuse, diazepam, diazoxide, folic acid, reserpine, rifampin, St. John’s wort^b, theophylline
Drugs that may either increase or decrease phenytoin serum levels
Antiepileptic drugs	Phenobarbital, valproate sodium, valproic acid

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion–the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide(including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide(including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄, and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5’-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.

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Table 8: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.6)] .
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were coadministered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported . Monitor blood glucose when ciprofloxacin is coadministered with oral antidiabetic drugs [see Adverse Reactions (6.1)] .
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is coadministered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after coadministration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after coadministration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution 2-fold increase in exposure	Monitor for sildenafil toxicity [see Pharmacokinetics (12.3)] .
Duloxetine	Avoid Use 5-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx ^®‡ (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2)].	Decrease ciprofloxacin absorption, resulting in lower serum and urine levels.
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

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Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio*)		Risperidone Dose recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose.
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg twice daily	1 mg single dose	1.1	0.94	Dose adjustment not needed

Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Table 3: Summary of AED interactions with Topiramate
AED Co-administered	AED Concentration	Topiramate Concentration
a = Plasma concentration increased 25% in some patients, generally those on a b.i.d. dosing regimen of phenytoin. b = Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. AED = Antiepileptic drug. NE = Not Evaluated. TPM – Topiramate
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC 40%	decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	15% increase

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( 7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( 7)
Phenytoin	Monitor phenytoin level ( 7)
Methotrexate	Monitor for methotrexate toxicity ( 7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine ( 7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin ( 7)

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. ₄ ₃
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT , is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. ₄ ₄ ₄ ₄ ₃ ₄ ₄ ₄
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. ₄
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T to T , leading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T and T levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). ₄ ₃ ₃ ₄ ₃ ₄ ₃ ₄ ₃ ₄
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of I, I, and Tc. ¹²³ ¹³¹ ^99m
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Figure 1: Effect of interacting drugs on the pharmacokinetics of venlafaxine and active metabolite O-desmethylvenlafaxine (ODV).

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin	Monitor phenytoin level (7)
Methotrexate	Monitor for methotrexate toxicity (7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)

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AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxideIs not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Concomitant Drug	Effect onConcentration ofLamotrigine orConcomitant Drug	Clinical Comment
Estrogen-containing oralcontraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine concentrationsapproximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepineand carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentrationapproximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUCapproximately 32%.

Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold.There are conflicting study resultsregarding effect of lamotrigine onvalproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change invalproate concentrations in controlled clinical trials in patients with epilepsy.

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Drug	Description
Heparin	Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients
Pyrazinamide	Inhibits pyrazinamide-induced hyperuricemia
Uricosuric Agents	Effect of probenecid, sulfinpyrazone and phenylbutazone inhibited

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Phenylephrine:
Drug	Effect
Phenylephrine with prior administration of monoamine oxidase inhibitors (MAOI).	Cardiac pressor response potentiated. May cause acute hypertensive crisis.

Phenylephrine with tricyclic antidepressants.	Pressor response increased.

Phenylephrine with ergot alkaloids.	Excessive rise in blood pressure.

Phenylephrine with bronchodilator sympathomimetic agents and with epinephrine or other sympathomimetics.	Tachycardia or other arrhythmias may occur.

Phenylephrine with prior administration of propranolol or other β-adrenergic blockers.	Cardiostimulating effects blocked.

Phenylephrine with atropine sulfate.	Reflex bradycardia blocked; pressor response enhanced.

Phenylephrine with prior administration of phentolamine or other α-adrenergic blockers.	Pressor response decreased.

Phenylephrine with diet preparations, such as amphetamines or phenylpropanolamine.	Synergistic adrenergic response.

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Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol,can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.The depressant effects of morphine are potentiated by the presence of other CNS depressants. Use of neuroleptics in conjunction with neuraxial morphine may increase the risk of respiratory depression.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.5) ].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, physotropic drugs, antihistamines, neuroleptics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue DURAMORPH if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.9)].
Intervention:	Do not use DURAMORPH in patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of other opioids (such as oxycodone, hydrocodone, oxymorphone, hydrocodone, or buprenorphine) to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:		May reduce the analgesic effect of DURAMORPH and/or precipitate withdrawal symptoms.
Intervention:		Avoid concomitant use.
Examples:		Butorphanol, nalbuphine, pentazocine, buprenorphine.
Muscle Relaxants
Clinical Impact:		Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:		Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of DURAMORPH and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:		Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:		Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:		The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:		Monitor patients for signs of urinary retention or reduced gastric motility when DURAMORPH is used concomitantly with anticholinergic drugs.

Table name:

Drugs That Interfere with Hemostasis
Clinical Impact:	Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen sodium and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of NAPRELAN with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention:	Concomitant use of NAPRELAN and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. NAPRELAN is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of NAPRELAN and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of NAPRELAN and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of NAPRELAN with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of NAPRELAN and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of NAPRELAN and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of NAPRELAN and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of NAPRELAN and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of NAPRELAN and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention:	The concomitant use of naproxen sodium with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of NAPRELAN and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of NAPRELAN and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicityNSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxid, and sucralfate with NAPRELAN is not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with NAPRELAN is not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving NAPRELAN and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:	Patients simultaneously receiving NAPRELAN and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

Table name:

Figure 1: Effect of interacting drugs on the pharmacokinetics of venlafaxine and active metabolite O-desmethylvenlafaxine (ODV).

Table name:

Concomitant Drug	Effect onConcentration ofLamotrigine orConcomitant Drug	Clinical Comment
Estrogen-containing oralcontraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine concentrationsapproximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepineand carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentrationapproximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUCapproximately 32%.

Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold.There are conflicting study resultsregarding effect of lamotrigine onvalproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change invalproate concentrations in controlled clinical trials in patients with epilepsy.

Table name:

Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours (two times the recommended twice daily dose) in healthy volunteers (n=24)
Concomitant Drug	C_maxSS (Peak plasma concentration)	AUC_ss(0–12h) (Extent of systemic exposure)
Erythromycin (500 mg every 8 hrs)	+82%	+109%
Ketoconazole (400 mg once daily)	+135%	+164%

Table name:

Table 3Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

Table name:

Factors	Dosage Adjustments for Aripiprazole
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors	Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double usual dose over 1 to 2 weeks

Table name: Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.During concomitant use of indomethacin capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of indomethacin capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.

Table 2 Clinically Significant Drug Interactions with Indomethacin
Drugs That Interfere with Hemostasis
Clinical Impact:
Intervention:	Monitor patients with concomitant use of indomethacin capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention:	Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Indomethacin capsules are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:
Intervention:
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. It has been reported that the addition of triamterene to a maintenance schedule of indomethacin capsules resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin capsules and triamterene should not be administered together. Both indomethacin capsules and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin capsules and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently.
Intervention:	Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact:	The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin. [see Clinical Pharmacology (12.3)]. In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage.
Intervention:	The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed‑associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Probenecid
Clinical Impact:	When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased.
Intervention:	During the concomitant use of indomethacin capsules and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments.

Table name:

Table 3: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in BPH patients on stable alpha-blocker therapy with tamsulosin 0.4 or 0.8 mg daily (Study 2)
	Vardenafil 10 mg Placebo-subtracted	Vardenafil 20 mg Placebo-subtracted
Standing SBP	-4 (-6.8, -0.3)	-4 (-6.8, -1.4)
Supine SBP	-5 (-8.2, -0.8)	-4 (-6.3, -1.8)

Table name:

Drugs That Interfere with Hemostasis
Clinical Impact:	• Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	• During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

Table name:

Concomitant Drug	Effect onConcentration ofLamotrigine orConcomitant Drug	Clinical Comment
Estrogen-containing oralcontraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine concentrationsapproximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepineand carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentrationapproximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUCapproximately 32%.

Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold.There are conflicting study resultsregarding effect of lamotrigine onvalproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change invalproate concentrations in controlled clinical trials in patients with epilepsy.

Table name:

Antiretrovirals
Clinical Impact:	The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3)]. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)]. There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
Intervention:	Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications (4)]. Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:	Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention:	Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact:	Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].
Intervention:	A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact:	Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)]. There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention:	Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6)].
Citalopram
Clinical Impact:	Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention:	Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:	Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].
Intervention:	Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:	Potential for increased exposure of phenytoin.
Intervention:	Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:	Increased exposure of diazepam [see Clinical Pharmacology (12.3)].
Intervention:	Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:	Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention:	Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:	Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:	Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)]. See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:	Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated.
	Amoxicillin also has drug interactions.
Intervention:	See Contraindications, Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact:	Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention:	Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:	Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10), Clinical Pharmacology (12.2)].
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:	Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact:	There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:	An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:	There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:	Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.

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AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide Is not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Table 13. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Table 9: Drugs That are Affected by and Affecting Ciprofloxacin Tablets
Drugs That are Affected by C iprofloxacin Tablets
Drug(s)	Recommendation		Comments
Tizanidine	Contraindicated		Concomitant administration of tizanidine and ciprofloxacin tablets is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [ see Contraindications ( 4.2 )]
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)		Concurrent administration of ciprofloxacin tablets with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [s ee Warnings and Precautions ( 5.9 ) ] .
Drugs Known to Prolong QT Interval	Avoid Use		Ciprofloxacin tablets may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions ( 5.11 ) and Use in Specific Populations ( 8.5 )].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated		Hypoglycemia sometimes severe has been reported when ciprofloxacin tablets and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin tablets is co-administered with oral antidiabetic drugs [see Adverse Reactions ( 6.1)].
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)		To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin tablets discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin tablets with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)		Monitor renal function (in particular serum creatinine) when ciprofloxacin tablets is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)		The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin tablets to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin tablets with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels		Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin tablets therapy is indicated.
Ropinirole	Use with caution		Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin tablets [ see Warnings and Precautions ( 5.16 ) ] .
Clozapine	Use with caution		Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin tablets are advised.
NSAIDs	Use with caution		Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution Two-fold increase in exposure		Monitor for sildenafil toxicity [see clinical Pharmacology ( 12.3)].
Duloxetine	Avoid Use Five-fold increase in duloxetine exposure		If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life		Ciprofloxacin tablets inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin Tablets
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)		Ciprofloxacin tablets should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration ( 2.4 ) ] .		Decrease ciprofloxacin tablets absorption, resulting in lower serum and urine levels
Probenecid		Use with caution (interferes with renal tubular secretion of ciprofloxacin tablets and increases ciprofloxacin tablets serum levels)		Potentiation of ciprofloxacin tablets toxicity may occur.

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Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio Change relative to reference)		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	Cmax	Risperidone Dose Recommendation
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Table 9 Established and Other Potentially Significant Drug Interactions with Ganciclovir
Name of the Concomitant Drug	Change in the Concentration of Ganciclovir or Concomitant Drug	Clinical Comment
Zidovudine	↓ Ganciclovir ↑ Zidovudine	Zidovudine and valganciclovir hydrochloride each have the potential to cause neutropenia and anemia
Probenecid	↑ Ganciclovir	Patients taking probenecid and valganciclovir hydrochloride should be monitored for evidence of ganciclovir toxicity
Mycophenolate Mofetil (MMF)	↔ Ganciclovir (in patients with normal renal function) ↔ MMF (in patients with normal renal function)	Patients with renal impairment should be monitored carefully as levels of MMF metabolites and ganciclovir may increase
Didanosine	↓ Ganciclovir ↑ Didanosine	Patients should be closely monitored for didanosine toxicity

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NA – Not available/reported
Digoxin concentrations increased greater than 50%
	Digoxin Serum Concentration Increase	Digoxin AUC Increase	Recommendations
Amiodarone	70%	NA	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
Captopril	58%	39%
Clarithromycin	NA	70%
Dronedarone	NA	150%
Gentamicin	129-212%	NA
Erythromycin	100%	NA
Itraconazole	80%	NA
Lapatinib	NA	180%
Nitrendipine	57%	15%
Propafenone	NA	60-270%
Quinidine	100%	NA
Ranolazine	50%	NA
Ritonavir	NA	86%
Telaprevir	50%	85%
Tetracycline	100%	NA
Verapamil	50-75%	NA
Digoxin concentrations increased less than 50%
Atorvastatin	22%	15%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
Carvedilol	16%	14%
Conivaptan	33%	43%
Diltiazem	20%	NA
Indomethacin	40%	NA
Nefazodone	27%	15%
Nifedipine	45%	NA
Propantheline	24%	24%
Quinine	NA	33%
Rabeprazole	29%	19%
Saquinavir	27%	49%
Spironolactone	25%	NA
Telmisartan	20-49%	NA
Ticagrelor	31%	28%
Tolvaptan	30%	20%
Trimethoprim	22-28%	NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate, sulfasalazine			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20-40% as necessary.

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DRUG	DESCRIPTION OF INTERACTION
Heparin	Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients.
Pyrazinamide	Inhibits pyrazinamide-induced hyperuricemia.
Uricosuric Agents	Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.

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Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	The concomitant use of SSRIs including sertraline hydrochloride and MAOIs increases the risk of serotonin syndrome.
Intervention:	Sertraline hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [See Dosage and Administration (2.5), Contraindications (4), Warnings and Precautions (5.2)].
Examples:	selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
Pimozide
Clinical Impact:	Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QT prolongation and ventricular arrhythmias.
Intervention:	Concomitant use of pimozide and sertraline hydrochloride is contraindicated [See Contraindications (4)].
Other Serotonergic Drugs
Clinical Impact:	The concomitant use of serotonergic drugs with sertraline hydrochloride increases the risk of serotonin syndrome.
Intervention:	Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of sertraline hydrochloride and/or concomitant serotonergic drugs [See Warnings and Precautions (5.2)].
Examples:	other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort
Drugs that Interfere with Hemostasis (antiplatelet agents and anticoagulants)
Clinical Impact:	The concurrent use of an antiplatelet agent or anticoagulant with sertraline hydrochloride may potentiate the risk of bleeding.
Intervention:	Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [See Warnings and Precautions (5.3)].
Examples:	aspirin, clopidogrel, heparin, warfarin
Drugs Highly Bound to Plasma Protein
Clinical Impact:	Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of sertraline hydrochloride with another drug that is highly bound to plasma protein may increase free concentrations of sertraline hydrochloride or other tightly-bound drugs in plasma [See Clinical Pharmacology (12.3)].
Intervention:	Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs as warranted.
Examples:	warfarin
Drugs Metabolized by CYP2D6
Clinical Impact:	Sertraline hydrochloride is a CYP2D6 inhibitor [See Clinical Pharmacology (12.3)]. The concomitant use of sertraline hydrochloride with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate.
Intervention:	Decrease the dosage of a CYP2D6 substrate if needed with concomitant sertraline hydrochloride use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride is discontinued.
Examples:	propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine
Phenytoin
Clinical Impact:	Phenytoin is a narrow therapeutic index drug. sertraline hydrochloride may increase phenytoin concentrations.
Intervention:	Monitor phenytoin levels when initiating or titrating sertraline hydrochloride. Reduce phenytoin dosage if needed.
Examples:	phenytoin, fosphenytoin

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TABLE 2. Mean (± S.D.) Pharmacokinetic Parameters for Estradiol, Estrone, and Equilin Following Coadministration of Conjugated Estrogens 0.625 mg and PROMETRIUM Capsules 200 mg for 12 Days to Postmenopausal Women
^a Total estrogens is the sum of conjugated and unconjugated estrogen.
	Conjugated Estrogens			Conjugated Estrogens plus PROMETRIUM Capsules
Drug	Cmax (ng/mL)	Tmax (hr)	AUC(0-24h) (ng × h/mL)	Cmax (ng/mL)	Tmax (hr)	AUC(0-24h) (ng × h/mL)
Estradiol	0.037 ± 0.048	12.7 ± 9.1	0.676 ± 0.737	0.030 ± 0.032	17.32 ± 1.21	0.561 ± 0.572
Estrone Total^a	3.68 ± 1.55	10.6 ± 6.8	61.3 ± 26.36	4.93 ± 2.07	7.5 ± 3.8	85.9 ± 41.2
Equilin Total^a	2.27 ± 0.95	6.0 ± 4.0	28.8 ± 13.0	3.22 ± 1.13	5.3 ± 2.6	38.1 ± 20.2

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( , , , ) 2.6 5.1 7 12.3
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C Protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 2. Steady-State Plasma Concentrations of Felbamate when Coadministered with Other AEDs
AED Coadministered	AED Concentration	Felbamate Concentration
Phenytoin	↑	↓
Valproate	↑	↔No significant effect.
Carbamazepine (CBZ) Not administered but an active metabolite of carbamazepine.CBZ epoxide	↓ ↑	↓
Phenobarbital	↑	↓

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol,	famotidine	nizatidine
systemic and inhaled	felodipine	norfloxacin
amoxicillin	finasteride	ofloxacin
ampicillin,	hydrocortisone	omeprazole
with or without	isoflurane	prednisone, prednisolone
sulbactam	isoniazid	ranitidine
atenolol	isradipine	rifabutin
azithromycin	influenza vaccine	roxithromycin
caffeine,	ketoconazole	sorbitol
dietary ingestion	lomefloxacin	(purgative doses do not
cefaclor	mebendazole	inhibit theophylline
co-trimoxazole	medroxyprogesterone	absorption)
(trimethoprim and	methylprednisolone	sucralfate
sulfamethoxazole)	metronidazole	terbutaline, systemic
diltiazem	metoprolol	terfenadine
dirithromycin	nadolol	tetracycline
enflurane	nifedipine	tocainide

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Interacting Drug	Interaction
Antacids, sucralfate, multivitamins, and other products containing multivalent cations	Moxifloxacin absorption is decreased. Administer AVELOX Tablet at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3, 17.2)
Warfarin	Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. (6.4, 7.2, 12.3)
Class IA and Class III antiarrhythmics:	Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.3, 7.4)

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Table 13. Established and Other Potentially Significant Drug Interactions
↓= Decreased (induces lamotrigine gluronidation). ↑= Increased (inhibits lamotrigine gluronidation). ?= Conflicting data.
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine ? CBZ epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Factors	Dosage Adjustments for Aripiprazole Tablets
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors	Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double usual dose over 1 to 2 weeks

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Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)	VIAGRA 100 mg
Supine	7.9 (4.6, 11.1)
Standing	4.3 (-1.8,10.3)

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2 fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
↓= Decreased (induces lamotrigine gluronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ?= Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
	? CBZ epoxide	May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Drugs That Interfere with Hemostasis
Clinical Impact:	• Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of naproxen delayed-release tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity ).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	Concomitant use of naproxen delayed-release tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen delayed-release tablets are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	• During concomitant use of naproxen delayed-release tablets and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen delayed-release tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention	During concomitant use of naproxen delayed-release tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of naproxen delayed-release tablets and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen delayed-release tablets and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen delayed-release tablets and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen delayed-release tablets and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen delayed-release tablets and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen delayed-release tablets and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of naproxen delayed-release tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen delayed-release tablets is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed-release tablets is not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxen delayed-release tablets is not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen delayed-release tablets and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:	Patients simultaneously receiving naproxen delayed-release tablets and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

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Table 6: Predicted Drug Interactions with Didanosine Delayed-Release Capsules
Drug or Drug Class	Effect	Clinical Comment
↑ Indicates increase. ^a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of didanosine delayed-release capsules is recommended [see Warnings and Precautions (5.1)]. ^b [See Warnings and Precautions (5.6).]
Drugs that may cause pancreatic toxicity	↑ risk of pancreatitis	Use only with extreme caution.^a
Neurotoxic drugs	↑ risk of neuropathy	Use with caution.^b

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Table 4 Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class: Drug Name	Effect on Concentration	Clinical Comment
Antacids: antacids (e.g., aluminium, magnesium hydroxide, or calcium carbonate)	↔ rilpivirine (antacids taken at least 2 hours before or at least 4 hours after rilpivirine) ↓ rilpivirine (concomitant intake)	The combination of COMPLERA and antacids should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). Antacids should only be administered either at least 2 hours before or at least 4 hours after COMPLERA.
Azole Antifungal Agents: fluconazole itraconazole ketoconazole posaconazole voriconazole	↑ rilpivirineThe interaction was evaluated in a clinical study. All other drug-drug interactions shown are predicted. ^, This interaction study has been performed with a dose higher than the recommended dose for rilpivirine. The dosing recommendation is applicable to the recommended dose of rilpivirine 25 mg once daily. ↓ ketoconazole ^,	Concomitant use of COMPLERA with azole antifungal agents may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when COMPLERA is coadministered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are coadministered with COMPLERA.
H₂-Receptor Antagonists: cimetidine famotidine nizatidine ranitidine	↔ rilpivirine ^, (famotidine taken 12 hours before rilpivirine or 4 hours after rilpivirine) ↓ rilpivirine ^, (famotidine taken 2 hours before rilpivirine)	The combination of COMPLERA and H₂-receptor antagonists should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). H₂-receptor antagonists should only be administered at least 12 hours before or at least 4 hours after COMPLERA.
Macrolide or Ketolide Antibiotics: clarithromycin erythromycin telithromycin	↑ rilpivirine ↔ clarithromycin ↔ erythromycin ↔ telithromycin	Concomitant use of COMPLERA with clarithromycin, erythromycin or telithromycin may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Where possible, alternatives such as azithromycin should be considered.
Narcotic Analgesics: methadone	↓ R(–) methadone ↓ S(+) methadone ↔ rilpivirine ↔ methadone (when used with tenofovir)	No dose adjustments are required when initiating coadministration of methadone with COMPLERA. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients.

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albuterol, systemic and inhaled	mebendazole
amoxicillin	medroxyprogesterone
ampicillin, with or without	methylprednisolone
sulbactam	metronidazole
atenolol	metoprolol
azithromycin	nadolol
caffeine, dietary ingestion	nifedipine
cefaclor	nizatidine
co-trimoxazole (trimethoprim and sulfamethoxazole)	norfloxacin
co-trimoxazole (trimethoprim and sulfamethoxazole)	ofloxacin
diltiazem	omeprazole
dirithromycin	prednisone, prednisolone
enflurane	ranitidine
famotidine	rifabutin
felodipine	roxithromycin
finasteride	Sorbitol (purgative doses do not inhibit
hydrocortisone	theophylline absorption)
isoflurane	sucralfate
isoniazid	terbutaline, systemic
isradipine	terfenadine
influenza vaccine	tetracycline
ketoconazole	tocainide
lomefloxacin

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
↓= Decreased (induces lamotrigine glucuronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ? = Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine concentrations approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine and carbamazepine epoxide	? carbamazepine epoxide	May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Table 3 Clinically Relevant Interactions Affecting Drugs Co-Administered with Omeprazole and Interaction with Diagnostics
Antiretrovirals
Clinical Impact :	The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
	o Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3)].
	o Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see clinical Pharmacology (12.3)].
	o There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
Intervention :	Rilpivirine-containing products: Concomitant use with omeprazole delayed-release capsule is contraindicated [see Contraindications (4)].
	Atazanavir: Avoid concomitant use with omeprazole delayed-release capsules. See prescribing information for atazanavir for dosing information.
	Nelfinavir: Avoid concomitant use with omeprazole delayed-release capsules. See prescribing information for nelfinavir.
	Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities.
	Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact :	Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention :	Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact :	Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].
Intervention :	A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates ( e . g ., clopidogrel , citalopram , cilostazol , phenytoin , diazepam )
Clopidogrel
Clinical Impact :	Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)]. There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention :	Avoid concomitant use with omeprazole delayed-release capsules. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6)].
Citalopram
Clinical Impact :	Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention :	Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact :	Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].
Intervention :	Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact :	Potential for increased exposure of phenytoin.
Intervention :	Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact :	Increased exposure of diazepam [see Clinical Pharmacology (12.3)].
Intervention :	Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact :	Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention :	Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption ( e . g ., iron salts , erlotinib , dasatinib , nilotinib , mycophenolate mofetil , ketoconazole / itraconazole )
Clinical Impact :	Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention :	Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole delayed-release capsules and MMF. Use omeprazole delayed-release capsules with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)]. See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact :	Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention :	See Contraindications , Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact :	Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention :	Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact :	Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10), Clinical Pharmacology (12.2)].
Intervention :	Temporarily stop omeprazole delayed-release capsules treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact :	Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention :	Temporarily stop omeprazole delayed-release capsules treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact :	There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention :	An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact :	There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention :	Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole delayed-release capsules.

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Interacting Drug	Interaction
Drugs known to prolong QT interval (e.g., Class IA and Class III antiarrhythmic agents).	QUALAQUIN prolongs QT interval, ECG abnormalities including QT prolongation and Torsades des Pointes. Avoid concomitant use (5.3).
Other antimalarials (e.g., halofantrine, mefloquine).	ECG abnormalities including QT prolongation. Avoid concomitant use (5.3, 7.2).
CYP3A4 inducers or inhibitors	Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine (7.1).
CYP3A4 and CYP2D6 substrates	Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the co-administered drug (7.1).
Digoxin	Increased digoxin plasma concentration (5.8, 7.1).

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Figure 2: Effect of venlafaxine on the pharmacokinetics interacting drugs and their active metabolites.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2) ].
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate. [See Warnings and Precautions (5.9) .]
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.11) and Use in Specific Populations (8.5) ].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [See Adverse Reactions (6.1) .]
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions (5.16) ].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies in and postmarketing.
Sildenafil	Use with caution Two-fold increase in exposure	Monitor for sildenafil toxicity (see Clinical Pharmacology (12.3 )].
Duloxetine	Avoid Use Five-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx^®(didanosine) chewable/ buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2.4)] .	Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

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Table 1: Clinically Significant Drug Interactions with DILAUDID
Benzodiazepines and other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.5)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue DILAUDID Oral Solution or DILAUDID Tablets if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.3)]. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Intervention:	The use of DILAUDID Oral Solution or DILAUDID Tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of DILAUDID Oral Solution or DILAUDID Tablets and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine,
Muscle Relaxants
Clinical Impact:	Hydromorphone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of DILAUDID Oral Solution or DILAUDID Tablets and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when DILAUDID Oral Solution or DILAUDID Tablets is used concomitantly with anticholinergic drugs.

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Table 5: Effect of Other Drugs on VYVANSE
Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Acidifying and Alkalinizing Agents	Ascorbic acid and other agents that acidify urine increase urinary excretion and decrease the half-life of amphetamine. Sodium bicarbonate and other agents that alkalinize urine decrease urinary excretion and extend the half-life of amphetamine.	Adjust the dose accordingly [see Dosage and Administration (2.6)]

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Table 3Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Table II. Clinically significant drug interactions with theophylline*.
Drug	Type of Interaction	Effect**
Adenosine	Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.
Alcohol	A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours.	30% increase
Allopurinol	Decreases theophylline clearance at allopurinol doses ≥600 mg/day.	25% increase
Aminoglutethimide	Increases theophylline clearance by induction of microsomal enzyme activity.	25% decrease
Carbamazepine	Similar to aminoglutethimide.	30% decrease
Cimetidine	Decreases theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase
Ciprofloxacin	Similar to cimetidine.	40% increase
Clarithromycin	Similar to erythromycin.	25% increase
Diazepam	Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.	Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram	Decreases theophylline clearance by inhibiting hydroxylation and demethylation.	50% increase
Enoxacin	Similar to cimetidine.	300% increase
Ephedrine	Synergistic CNS effects	Increased frequency of nausea, nervousness, and insomnia.
Erythromycin	Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-stateserum concentrations decrease by a similar amount.
Estrogen	Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.	30% increase
Flurazepam	Similar to diazepam.	Similar to diazepam.
Fluvoxamine	Similar to cimetidine.	Similar to cimetidine.
Halothane	Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.	Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A	Decreases theophylline clearance.	100% increase
Isoproterenol (IV)	Increases theophylline clearance.	20% decrease
Ketamine	Pharmacologic	May lower theophylline seizure threshold.
Lithium	Theophylline increases renal lithium clearance.	Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam	Similar to diazepam.	Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.	20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine	Similar to disulfiram.	80% increase
Midazolam	Similar to diazepam.	Similar to diazepam.
Moricizine	Increases theophylline clearance.	25% decrease
Pancuronium	Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.	Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline	Decreases theophylline clearance.	30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.	25% decrease after two weeks of concurrent PB.
Phenytoin	Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.	Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone	Decreases theophylline clearance and pharmacologic interaction.	40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and pharmacologic interaction.	100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin	Increases theophylline clearance by increasing cytochrome P4501A2 and 3A3 activity.	20-40% decrease
Sulfinpyrazone	Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.	20% decrease
Tacrine	Similar to cimetidine, also increases renal clearance of theophylline.	90% increase
Thiabendazole	Decreases theophylline clearance.	190% increase
Ticlopidine	Decreases theophylline clearance.	60% increase
Troleandomycin	Similar to erythromycin.	33-100% increase depending on troleandomycin dose.
Verapamil	Similar to disulfiram.	20% increase
* Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
** Average effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.

Table name:

Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin	Monitor phenytoin level (7)
Methotrexate	Monitor for methotrexate toxicity (7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)

Table name:

Table 7: Summary of AED Interactions with Oxcarbazepine

AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean change, 90% Confidence Interval)
Carbamazepine	400 to 2000	900	nc¹	40% decrease [Cl: 17% decrease, 57% decrease]
Phenobarbital	100 to 150	600 to 1800	14% increase [Cl: 2% increase, 24% increase]	25% decrease [Cl: 12% decrease, 51% decrease]
Phenytoin	250 to 500	600 to 1800 >1200 to 2400	nc^1,2 up to 40% increase³ [Cl: 12% increase, 60% increase]	30% decrease [Cl: 3% decrease, 48% decrease]
Valproic acid	400 to 2800	600 to 1800	nc¹	18% decrease [Cl: 13% decrease, 40% decrease]
¹nc denotes a mean change of less than 10% ²Pediatrics ³Mean increase in adults at high oxcarbazepine doses

Table name:

Table 13. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

Table name:

Drugs That Interfere with Hemostasis
Clinical Impact:	• Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	• During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

Table name:

Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin	Monitor phenytoin level (7)
Methotrexate	Monitor for methotrexate toxicity (7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)

Table name:

Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
* Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol, systemic and inhaled	hydrocortisone	ofloxacin
amoxicillin	isoflurane	omeprazole
ampicillin, with or without	isoniazid	prednisone, prednisolone
sulbactam	isradipine	ranitidine
atenolol	influenza vaccine	rifabutin
azithromycin	ketoconazole	roxithromycin
caffeine, dietary ingestion	lomefloxacin	sorbitol
cefaclor	mebendazole	(purgative doses do
co-trimoxazole (trimethoprim	medroxyprogesterone	not inhibit theophylline
and sulfamethoxazole)	methylprednisolone	absorption)
diltiazem	metronidazole	sucralfate
dirithromycin	metoprolol	terbutaline,systemic
enflurane	nadolol	terfenadine
famotidine	nifedipine	tetracycline
felodipine	nizatidine	tocainide
finasteride	norfloxacin

Table name: Use of sildenafil (REVATIO) is contraindicated when used for the treatment of PAH [see Contraindications (4)]. The following dose adjustments are recommended for use of tadalafil (ADCIRCA^®) with LEXIVA: Coadministration of ADCIRCA in patients on LEXIVA: In patients receiving LEXIVA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Coadministration of LEXIVA in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of LEXIVA. Stop ADCIRCA at least 24 hours prior to starting LEXIVA. After at least one week following the initiation of LEXIVA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: LEXIVA: Sildenafil: 25 mg every 48 hours. Tadalafil: no more than 10 mg every 72 hours. Vardenafil: no more than 2.5 mg every 24 hours. LEXIVA/ritonavir: Sildenafil: 25 mg every 48 hours.Tadalafil: no more than 10 mg every 72 hours.Vardenafil: no more than 2.5 mg every 72 hours.Use with increased monitoring for adverse events.

Table 7. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug Name	Effect on Concentration of Amprenavir or Concomitant Drug	Clinical Comment
HCV/HIV-Antiviral Agents
HCV protease inhibitor: Boceprevir	LEXIVA: ↓Amprenavir (predicted) ↔ or ↓Boceprevir (predicted) LEXIVA/ritonavir: ↓Amprenavir (predicted) ↓Boceprevir (predicted)	Coadministration of LEXIVA or LEXIVA/ritonavir and boceprevir is not recommended.
HCV protease inhibitor: Simeprevir	LEXIVA: ↔Amprenavir (predicted) ↑ or ↓Simeprevir (predicted) LEXIVA/ritonavir: ↔Amprenavir (predicted) ↑Simeprevir (predicted)	Coadministration of LEXIVA or LEXIVA/ritonavir and simeprevir is not recommended.
HCV protease inhibitor: Paritaprevir (coformulated with ritonavir and ombitasvir and coadministered with dasabuvir)	LEXIVA: ↑Amprenavir (predicted) ↑ or ↔Paritaprevir (predicted) LEXIVA/ritonavir: ↑ or ↔Amprenavir (predicted) ↑Paritaprevir (predicted)	Appropriate doses of the combinations with respect to safety and efficacy have not been established. LEXIVA 1400 mg once daily may be considered when coadministered with paritaprevir/ritonavir/ombitasvir/ dasabuvir. Coadministration of LEXIVA/ritonavir and paritaprevir/ritonavir/ombitasvir/ dasabuvir is not recommended.
Non-nucleoside reverse transcriptase inhibitor: Efavirenz^a	LEXIVA: ↓Amprenavir LEXIVA/ritonavir: ↓Amprenavir	Appropriate doses of the combinations with respect to safety and efficacy have not been established. An additional 100 mg/day (300 mg total) of ritonavir is recommended when efavirenz is administered with LEXIVA/ritonavir once daily. No change in the ritonavir dose is required when efavirenz is administered with LEXIVA plus ritonavir twice daily.
Non-nucleoside reverse transcriptase inhibitor: Nevirapine^a	LEXIVA: ↓Amprenavir ↑Nevirapine LEXIVA/ritonavir: ↓Amprenavir ↑Nevirapine	Coadministration of nevirapine and LEXIVA without ritonavir is not recommended. No dosage adjustment required when nevirapine is administered with LEXIVA/ritonavir twice daily. The combination of nevirapine administered with LEXIVA/ritonavir once-daily regimen has not been studied.
HIV protease inhibitor: Atazanavir^a	LEXIVA: Interaction has not been evaluated. LEXIVA/ritonavir: ↓Atazanavir ↔Amprenavir	Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitors: Indinavir^a, nelfinavir^a	LEXIVA: ↑Amprenavir Effect on indinavir and nelfinavir is not well established. LEXIVA/ritonavir: Interaction has not been evaluated.	Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitors: Lopinavir/ritonavir^a	↓Amprenavir ↓Lopinavir	An increased rate of adverse events has been observed. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitor: Saquinavir^a	LEXIVA: ↓Amprenavir Effect on saquinavir is not well established. LEXIVA/ritonavir: Interaction has not been evaluated.	Appropriate doses of the combination with respect to safety and efficacy have not been established.
HIV integrase inhibitor: Raltegravir^a	LEXIVA: ↓Amprenavir ↓Raltegravir LEXIVA/ritonavir: ↓Amprenavir ↓Raltegravir	Appropriate doses of the combination with respect to safety and efficacy have not been established.
HIV integrase inhibitor: Dolutegravir^a	LEXIVA/ritonavir: ↓Dolutegravir	The recommended dose of dolutegravir is 50 mg twice daily when coadministered with LEXIVA/ritonavir. Use an alternative combination where possible in patients with known or suspected integrase inhibitor resistance.
HIV CCR5 co-receptor antagonist: Maraviroc^a	LEXIVA/ritonavir: ↓Amprenavir ↑Maraviroc	No dosage adjustment required for LEXIVA/ritonavir. The recommended dose of maraviroc is 150 mg twice daily when coadministered with LEXIVA/ritonavir. LEXIVA should be given with ritonavir when coadministered with maraviroc.
Other Agents
Antiarrhythmics: Amiodarone, lidocaine (systemic), and quinidine	↑Antiarrhythmics	Use with caution. Increased exposure may be associated with life-threatening reactions such as cardiac arrhythmias. Therapeutic concentration monitoring, if available, is recommended for antiarrhythmics.
Anticoagulant: Warfarin		Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: Carbamazepine, phenobarbital, phenytoin Phenytoin^a	LEXIVA: ↓Amprenavir LEXIVA/ritonavir: ↑Amprenavir ↓Phenytoin	Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations in patients taking these agents concomitantly. Plasma phenytoin concentrations should be monitored and phenytoin dose should be increased as appropriate. No change in LEXIVA/ritonavir dose is recommended.
Antidepressant: Paroxetine, trazodone	↓Paroxetine ↑Trazodone	Any paroxetine dose adjustment should be guided by clinical effect (tolerability and efficacy). Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as LEXIVA, the combination should be used with caution and a lower dose of trazodone should be considered.
Antifungals: Ketoconazole^a, itraconazole	↑Ketoconazole ↑Itraconazole	Increase monitoring for adverse events. LEXIVA: Dose reduction of ketoconazole or itraconazole may be needed for patients receiving more than 400 mg ketoconazole or itraconazole per day. LEXIVA/ritonavir: High doses of ketoconazole or itraconazole (greater than 200 mg/day) are not recommended.
Anti-gout: Colchicine	↑Colchicine	Patients with renal or hepatic impairment should not be given colchicine with LEXIVA/ritonavir. LEXIVA/ritonavir and coadministration of colchicine: Treatment of gout flares: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). LEXIVA and coadministration of colchicine: Treatment of gout flares: 1.2 mg (2 tablets) x 1 dose. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg twice a day or 0.6 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once a day. Treatment of FMF: Maximum daily dose of 1.2 mg (may be given as 0.6 mg twice a day).
Antimycobacterial: Rifabutin^a	↑Rifabutin and rifabutin metabolite	A complete blood count should be performed weekly and as clinically indicated to monitor for neutropenia. LEXIVA: A dosage reduction of rifabutin by at least half the recommended dose is required. LEXIVA/ritonavir: Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (a maximum dose of 150 mg every other day or 3 times per week).
Antipsychotics: Quetiapine	LEXIVA/ritonavir: ↑Quetiapine	Initiation of LEXIVA with ritonavir in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine drug exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking LEXIVA with ritonavir: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
Lurasidone	↑Lurasidone	LEXIVA: If coadministration is necessary, reduce the lurasidone dose. Refer to the lurasidone prescribing information for concomitant use with moderate CYP3A4 inhibitors. LEXIVA/ritonavir: Use of lurasidone is contraindicated.
Benzodiazepines: Alprazolam, clorazepate, diazepam, flurazepam	↑Benzodiazepines	Clinical significance is unknown. A decrease in benzodiazepine dose may be needed.
Calcium channel blockers: Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine	↑Calcium channel blockers	Use with caution. Clinical monitoring of patients is recommended.
Corticosteroid: Dexamethasone	↓Amprenavir	Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations.
Endothelin-receptor antagonists: Bosentan	↑Bosentan	Coadministration of bosentan in patients on LEXIVA: In patients who have been receiving LEXIVA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Coadministration of LEXIVA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of LEXIVA. After at least 10 days following the initiation of LEXIVA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Histamine H₂-receptor antagonists: Cimetidine, famotidine, nizatidine, ranitidine^a	LEXIVA: ↓Amprenavir LEXIVA/ritonavir: Interaction not evaluated	Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations.
HMG-CoA reductase inhibitors: Atorvastatin^a	↑Atorvastatin	Titrate atorvastatin dose carefully and use the lowest necessary dose; do not exceed atorvastatin 20 mg/day.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus	↑Immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents.
Inhaled beta-agonist: Salmeterol	↑Salmeterol	Concurrent administration of salmeterol with LEXIVA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Inhaled/nasal steroid: Fluticasone	LEXIVA: ↑Fluticasone LEXIVA/ritonavir: ↑Fluticasone	Use with caution. Consider alternatives to fluticasone, particularly for long-term use. May result in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone. Coadministration of fluticasone and LEXIVA/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
Narcotic analgesic: Methadone	↓Methadone	Data suggest that the interaction is not clinically relevant; however, patients should be monitored for opiate withdrawal symptoms.
Oral contraceptives: Ethinyl estradiol/norethindrone^a	LEXIVA: ↓Amprenavir ↓Ethinyl estradiol LEXIVA/ritonavir: ↓Ethinyl estradiol	Alternative methods of non-hormonal contraception are recommended. May lead to loss of virologic response.^a Increased risk of transaminase elevations. No data are available on the use of LEXIVA/ritonavir with other hormonal therapies, such as hormone replacement therapy (HRT) for postmenopausal women.
PDE5 inhibitors: Sildenafil, tadalafil, vardenafil	↑Sildenafil ↑Tadalafil ↑Vardenafil	May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):
Proton pump inhibitors: Esomeprazole^a, lansoprazole, omeprazole, pantoprazole, rabeprazole	LEXIVA: ↔Amprenavir ↑Esomeprazole LEXIVA/ritonavir: ↔Amprenavir ↔Esomeprazole	Proton pump inhibitors can be administered at the same time as a dose of LEXIVA with no change in plasma amprenavir concentrations.
Tricyclic antidepressants: Amitriptyline, imipramine	↑Tricyclics	Therapeutic concentration monitoring is recommended for tricyclic antidepressants.

Table name:

Increased Risk of Myopathy/Rhabdomyolysis (2, 5.1, 7, 12.3)
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
Lopinavir plus ritonavir	Use lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily






























Intervention:

Table name:

Table 2. Clinically Significant Drug Interactions with Diclofenac
Drugs That Interfere with Hemostasis
Clinical Impact:	•Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. •Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of diclofenac sodium delayed-release tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS: Hematologic Toxicity ).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ).
Intervention:	Concomitant use of diclofenac sodium delayed-release tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS: Hematologic Toxicity ). Diclofenac sodium delayed-release tablets are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	•NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). •In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	•During concomitant use of diclofenac sodium delayed-release tablets and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. •During concomitant use of diclofenac sodium delayed-release tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS: Renal Toxicity and Hyperkalemia ). •When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS: Renal Toxicity and Hyperkalemia ).
Digoxin
Clinical Impact:	The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of diclofenac sodium delayed-release tablets and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ).
Intervention:	The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of diclofenac sodium delayed-release tablets and pemetrexed may increase the risk of pemetrexed‑ associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or Inducers:
Clinical Impact:	Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Co-administration of diclofenac with CYP2C9 inhibitors (e.g. voriconazole) may enhance the exposure and toxicity of diclofenac whereas co‑administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of diclofenac.
Intervention:	A dosage adjustment may be warranted when diclofenac is administered with CYP2C9 inhibitors or inducers (see CLINICAL PHARMACOLOGY: Pharmacokinetics ).

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Drugs That Interfere with Hemostasis
Clinical Impact:	Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of diclofenac sodium topical gel with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention:	Concomitant use of diclofenac sodium topical gel and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Diclofenac sodium topical gel is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol) In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of diclofenac sodium topical gel and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of diclofenac sodium topical gel and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of diclofenac sodium topical gel with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact:	The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of diclofenac sodium topical gel and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of diclofenac sodium topical gel and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of diclofenac sodium topical gel and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of diclofenac sodium topical gel and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention:	During concomitant use of diclofenac sodium topical gel and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention:	The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of diclofenac sodium topical gel and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of diclofenac sodium topical gel and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and Gl toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.

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Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of aripiprazole tablets with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole tablets alone [see CLINICAL PHARMACOLOGY ( 12.3)].	With concomitant use of aripiprazole tablets with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole tablets dosage [see DOSAGE AND ADMINISTRATION ( 2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of aripiprazole tablets and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole tablets alone [see CLINICAL PHARMACOLOGY ( 12.3)].	With concomitant use of aripiprazole tablets with a strong CYP3A4 inducer, consider increasing the aripiprazole tablets dosage [see DOSAGE AND ADMINISTRATION ( 2.7)].
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS ( 5.8)].
Benzodiazepines (e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS ( 5.7)]	Monitor sedation and blood pressure. Adjust dose accordingly.

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Effects on Steady-State Fexofenadine Pharmacokinetics After 7 Days of Co-Administration with Fexofenadine Hydrochloride 120 mg Every 12 Hours (two times the recommended twice daily dose) in Healthy Volunteers (n=24)
Concomitant Drug	C_max SS (Peak plasma concentration)	AUC_SS(0–12h) (Extent of systemic exposure)
Erythromycin (500 mg every 8 hrs)	+82%	+109%
Ketoconazole (400 mg once daily)	+135%	+164%

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Table 4 Established and Other Potentially SignificantThis table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class: Drug Name	Effect	Clinical Comment
Antiretroviral agents
Protease inhibitor: atazanavir	↓atazanavir concentration ↑ tenofovir concentration	Coadministration of atazanavir with ATRIPLA is not recommended. Coadministration of atazanavir with either efavirenz or tenofovir DF decreases plasma concentrations of atazanavir. The combined effect of efavirenz plus tenofovir DF on atazanavir plasma concentrations is not known. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA.
Protease inhibitor: fosamprenavir calcium	↓ amprenavir concentration	Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and ATRIPLA with respect to safety and efficacy have not been established. Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when ATRIPLA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when ATRIPLA is administered with fosamprenavir plus ritonavir twice daily.
Protease inhibitor: indinavir	↓ indinavir concentration	The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz.
Protease inhibitor: lopinavir/ritonavir	↓ lopinavir concentration ↑ tenofovir concentration	A dose increase of lopinavir/ritonavir to 600/150 mg (3 tablets) twice daily may be considered when used in combination with efavirenz in treatment-experienced patients where decreased susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence). Patients should be monitored for tenofovir-associated adverse reactions. ATRIPLA should be discontinued in patients who develop tenofovir-associated adverse reactions.
Protease inhibitor: ritonavir	↑ ritonavir concentration ↑ efavirenz concentration	When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when ATRIPLA is used in combination with ritonavir.
Protease inhibitor: saquinavir	↓ saquinavir concentration	Should not be used as sole protease inhibitor in combination with ATRIPLA.
NRTI: didanosine	↑ didanosine concentration	Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis and neuropathy. In adults weighing >60 kg, the didanosine dose should be reduced to 250 mg if coadministered with ATRIPLA. Data are not available to recommend a dose adjustment of didanosine for patients weighing <60 kg. Coadministration of ATRIPLA and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions. For additional information, please consult the Videx / Videx EC (didanosine) prescribing information.
Other agents
Anticoagulant: warfarin	↑ or ↓ warfarin concentration	Plasma concentrations and effects potentially increased or decreased by efavirenz.
Anticonvulsants: carbamazepine	↓ carbamazepine concentration ↓ efavirenz concentration	There are insufficient data to make a dose recommendation for ATRIPLA. Alternative anticonvulsant treatment should be used.
phenytoin phenobarbital	↓ anticonvulsant concentration ↓ efavirenz concentration	Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
Antidepressant: sertraline	↓ sertraline concentration	Increases in sertraline dose should be guided by clinical response.
Antifungals: itraconazole	↓ itraconazole concentration ↓ hydroxy-itraconazole concentration	Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
ketoconazole	↓ ketoconazole concentration	Drug interaction studies with ATRIPLA and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole.
Anti-infective: clarithromycin	↓ clarithromycin concentration ↑ 14-OH metabolite concentration	Clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of ATRIPLA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with ATRIPLA.
Antimycobacterial: rifabutin	↓ rifabutin concentration	Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
Antimycobacterial: rifampin	↓ efavirenz concentration	Clinical significance of reduced efavirenz concentration is unknown. Dosing recommendations for concomitant use of ATRIPLA and rifampin have not been established.
Calcium channel blockers: diltiazem	↓ diltiazem concentration ↓ desacetyl diltiazem concentration ↓ N-monodes-methyl diltiazem concentration	Diltiazem dose adjustments should be guided by clinical response (refer to the prescribing information for diltiazem). No dose adjustment of ATRIPLA is necessary when administered with diltiazem.
Others (e.g., felodipine, nicardipine, nifedipine, verapamil)	↓ calcium channel blocker	No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the prescribing information for the calcium channel blocker).
HMG-CoA reductase inhibitors: atorvastatin pravastatin simvastatin	↓ atorvastatin concentration ↓ pravastatin concentration ↓ simvastatin concentration	Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with efavirenz. Consult the prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
Hormonal contraceptives:
Oral: Ethinyl estradiol/Norgestimate	↓ active metabolites of norgestimate	A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed.
Implant: Etonogestrel	↓ etonogestrel	A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A	↓ immuno-suppressant	Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by efavirenz. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with ATRIPLA.
Narcotic analgesic: methadone	↓ methadone concentration	Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.

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Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
*Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	Cmax
Enzyme (CYP2D6) inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not Needed

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DRUG	DISCRIPTION OF INTERACTION
Heparin	Salicylate decreases platelet adhesiveness and inteferes with hemostasis in heparin treated patients.
Pyrazinamide	Inhibits pyrazinamide induced hyperuricemia.
Uricosuric Agents	Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.

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Drugs that Affect Renal Function	A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics	Dofetilide	Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
	Sotalol	Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
	Dronedarone	Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog	Teriparatide	Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement	Thyroid	Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics	Epinephrine Norepinephrine Dopamine	Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents	Succinylcholine	May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements	Calcium	If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers		Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.

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Table II. Clinically significant drug interactions with theophylline.Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
Drug	Type of Interaction	EffectAverage effect on steady-state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine	Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.
Alcohol	A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours	30% increase
Allopurinol	Decreases theophylline clearance at allopurinol doses ≥ 600 mg/day	25% increase
Aminoglutethimide	Increases theophylline clearance by induction of microsomal enzyme activity.	25% decrease
Carbamazepine	Similar to aminoglutethimide.	30% decrease
Cimetidine	Decreases theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase
Ciprofloxacin	Similar to cimetidine.	40% increase
Clarithromycin	Similar to erythromycin.	25% increase
Diazepam	Benzodiazepines increase CNS concentratrions of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.	Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram	Decreases theophylline clearance by inhibiting hydroxylation and demethylation.	50% increase
Enoxacin	Similar to cimetidine.	300% increase
Ephedrine	Synergistic CNS effects	Increased frequency of nausea, nervousness, and insomnia.
Erythromycin	Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen	Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance in unknown.	30% increase
Flurazepam	Similar to diazepam.	Similar to diazepam.
Fluvoxamine	Similar to cimetidine.	Similar to cimetidine.
Halothane	Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.	Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A	Decreases theophylline clearance.	100% increase
Isoproterenol (IV)	Increase theophylline clearance.	20% increase
Ketamine	Pharmacologic	May lower theophylline seizure threshold.
Lithium	Theophylline increases renal lithium clearance.	Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam	Similar to diazepam.	Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.	20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine	Similar to disulfiram.	80% increase
Midazolam	Similar to diazepam.	Similar to diazepam.
Moricizine	Increases theophylline clearance.	25% increase
Pancuronium	Theophylline may antagonize non-depolarizing neuromuscular blocking effects;possibly due to phosphodiesterase inhibition.	Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline	Decreases theophylline clearance.	30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.	25% decrease after two weeks of concurrent PB.
Phenytoin	Phenytoin increases theophylline clearance by increasing microsomal enzyme activity.	Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone	Decreases theophylline clearance and pharmacologic interaction.	40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and pharmacologic interaction.	100% increase Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin	Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.	20-40% decrease
Sulfinpyrazone	Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.	20% increase
Tacrine	Similar to cimetidine, also increases renal clearance of theophylline.	90% increase
Thiabendazole	Decreases theophylline clearance.	190% increase
Ticlopidine	Decreases theophylline clearance.	60% increase
Troleandomycin	Similar to erythromycin.	33-100% increase depending on troleandomycin dose.
Verapamil	Similar to disulfiram.	20% increase

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Table 7: Summary of AED Interactions with Oxcarbazepine
¹nc denotes a mean change of less than 10%
²Pediatrics
³Mean increase in adults at high oxcarbazepine doses
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400 to 2000	900	nc¹	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100 to150	600 to 1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250 to 500	600 to 1800 >1200 to 2400	nc^1,2 up to 40% increase³ [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400 to 2800	600 to 1800	nc¹	18% decrease [CI: 13% decrease, 40% decrease]
Lamotrigine	200	1200	nc¹	nc¹

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistatcontaining products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin dailyFor patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Table 8: Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]
* Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects * Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30 to 100 mg q24h) ** Non-Steroidal Anti-Inflammatory Drug *** Non-Nucleoside Reverse Transcriptase Inhibitors
Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C_max and AUC _τ )	Recommendations for Drug Dosage Adjustment/Comments
Sirolimus* (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin* (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (400 mg q24h) (CYP3A4 Inhibition) Efavirenz (300 mg q24h) (CYP3A4 Inhibition)	Significantly Increased Slight Increase in AUC_τ	Contraindicated When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)(CYP3A4 Inhibition) Low-dose Ritonavir (100 mg q12h)	No Significant Effect of Voriconazole on Ritonavir C_max or AUC_τ Slight Decrease in Ritonavir C_max and AUC_τ	Contraindicated because of significant reduction of voriconazole C_max and AUC_τ Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole C_max and AUC_τ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated
Cyclosporine* (CYP3A4 Inhibition)	AUC_τ Significantly Increased; No Significant Effect on C_max	When initiating therapy with voriconazole in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
Methadone*** (CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7) ]
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see Drug Interactions (7) ].
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7) ].
NSAIDs**** including. ibuprofen and diclofenac (CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [see Drug Interactions (7) ].
Tacrolimus* (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with voriconazole in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin* (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)**	Increased	Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin* (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	Monitor PT or other suitable anti- coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole* (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with voriconazole in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects on Indinavir Exposure In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	No dosage adjustment for indinavir when coadministered with voriconazole Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIs***** (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.
Everolimus (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Concomitant administration of voriconazole and everolimus is not recommended.

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Table 6. Established and Other Potentially Significant Drug Interactions with Ganciclovir
Name of the Concomitant Drug	Change in the Concentration of Ganciclovir or Concomitant Drug	Clinical Comment
Didanosine	↑ Didanosine	Patients should be closely monitored for didanosine toxicity.
Zidovudine	↓ Ganciclovir ↑ Zidovudine	Dose reduction or interruption may be needed because both zidovudine and ganciclovir have the potential to cause neutropenia and anemia. Monitor with frequent tests of white blood cell counts with differential and hemoglobin levels.
Probenecid	↑ Ganciclovir	GANCICLOVIR INJECTION dose may need to be reduced. Monitor for evidence of ganciclovir toxicity.
Imipenem-cilastatin	Unknown	Coadministration with imipenem-cilastatin is not recommended because generalized seizures have been reported in patients who received ganciclovir and imipenem-cilastatin.
Cyclosporine or amphotericin B	Unknown	Monitor renal function when GANCICLOVIR INJECTION is co-administered with cyclosporine or amphotericin B because of potential increase in serum creatinine [see Warnings and Precautions (5.2)].
Dapsone, pentamidine, flucytosine, vincristine, vinblastine, adriamycin, amphotericin B, trimethoprim/sulfamethoxazole combinations or other nucleoside analogues	Unknown	Co-administration with GANCICLOVIR INJECTION should be considered only if the potential benefits are judged to outweigh the risks because of potential additive toxicity.

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Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety(Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone DoseRecommendation
	Coadministered Drug	Risperidone	AUC	C_max
Enzyme (CYP2D6)Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Donot exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-	Re-evaluate dosing. Do not exceed 8 mg/day
Enzyme (CYP3A/PgP inducers)Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards.Do not exceed twice the patient’s usual dose
Enzyme (CYP3A)Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed

Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Antibiotics	Antineoplastics	Anti-inflammatory Drugs	Gastrointestinal Agents
ciprofloxacin	melphalan	Azapropazon	cimetidine
gentamicin		Colchicine	ranitidine
tobramycin	Antifungals	Diclofenac
vancomycin	amphotericin B	Naproxen	Immunosuppressives
trimethoprim with sulfamethoxazole	ketoconazole	Sulindac	tacrolimus

			Other Drugs
			fibric acid derivatives (e.g., bezafibrate, fenofibrate)
			methotrexate

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Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 3. Comparison of Clopidogrel Active Metabolite Exposure and Platelet Inhibition with and without Proton Pump Inhibitors, Omeprazole and Pantoprazole

	% Change from Plavix (300 mg/75 mg) alone
Plavix plus	C_max (ng/mL)		AUC		Platelet InhibitionInhibition of platelet aggregation with 5 mcM ADP (%)
	Day 1	Day 5	Day 1	Day 5AUC at Day 5 is AUC_0–24	Day 1	Day 5
OmeprazoleSimilar results seen when Plavix and omeprazole were administered 12 hours apart. 80 mg	↓46%	↓42%	↓45%	↓40%	↓39%	↓21%
Pantoprazole 80 mg	↓24%	↓28%	↓20%	↓14%	↓15%	↓11%

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Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. The depressant effects of morphine are potentiated by the presence of other CNS depressants. Use of neuroleptics in conjunction with neuraxial morphine may increase the risk of respiratory depression.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.5)].
Examples:	Alcohol, benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, psychotropic drugs, antihistamines, neuroleptics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue INFUMORPH if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.9)].
Intervention:	Do not use INFUMORPH in patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of other opioids (such as oxycodone, hydrocodone, oxymorphone, hydrocodone, or buprenorphine) to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of INFUMORPH and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	Butorphanol, nalbuphine, pentazocine, buprenorphine.
Muscle Relaxants
Clinical Impact:	Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of INFUMORPH and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation,which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when INFUMORPH is used concomitantly with anticholinergic drugs.

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Table 2: Clinically Significant Drug Interactions with Oxaprozin Drugs That Interfere with Hemostasis
Clinical Impact:	Oxaprozin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of oxaprozin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of oxaprozin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11 )].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention:	Concomitant use of oxaprozin and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Oxaprozin is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of oxaprozin and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of oxaprozin and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of oxaprozin with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact:	The concomitant use of oxaprozin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of oxaprozin and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of oxaprozin and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction) because NSAID administration may result in increased plasma levels of methotrexate, especially in patients receiving high doses of methotrexate.
Intervention:	During concomitant use of oxaprozin and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of oxaprozin and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of oxaprozin and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of oxaprozin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention:	The concomitant use of oxaprozin with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of oxaprozin and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of oxaprozin and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Corticosteroids
Clinical Impact:	Concomitant use of corticosteroids with oxaprozin may increase the risk of GI ulceration or bleeding.
Intervention:	Monitor patients with concomitant use of oxaprozin with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)].
Glyburide
Clinical Impact:	While oxaprozin does alter the pharmacokinetics of glyburide, coadministration of oxaprozin to type II non-insulin dependent diabetic patients did not affect the area under the glucose concentration curve nor the magnitude or duration of control.
Intervention:	During concomitant use of oxaprozin and glyburide, monitor patient’s blood glucose in the beginning phase of cotherapy.

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Factors	Dosage Adjustment of Aripiprazole tablets
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
KnownCYP2D6Poor Metabolizersand strongCYP3A4 inhibitors	Administer a quarter of usualdose
StrongCYP2D6 or CYP3A4inhibitors	Administerhalf of usual dose
StrongCYP2D6andCYP3A4 inhibitors	Administer a quarter of usualdose
StrongCYP3A4inducers	Double usual doseover 1 to 2 weeks

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AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxideIs not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine ? CBZ epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Specific Drugs Reported
also: diet high in vitamin K unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported.
alcohol† aminoglutethimide amobarbital atorvastatin† azathioprine butabarbital butalbital carbamazepine chloral hydrate† chlordiazepoxide chlorthalidone	cholestyramine† clozapine corticotropin cortisone cyclophosphamide† dicloxacillin ethchlorvynol glutethimide griseofulvin haloperidol meprobamate	6-mercaptopurine methimazole† moricizine hydrochloride† nafcillin paraldehyde pentobarbital phenobarbital phenytoin† pravastatin† prednisone† primidone	propylthiouracil† raloxifene ranitidine† rifampin secobarbital spironolactone sucralfate trazodone vitamin C (high dose) vitamin K warfarin underdosage

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albuterol, systemic and inhaled	mebendazole
amoxicillin	medroxyprogesterone
ampicillin, with or without	methylprednisolone
sulbactam	metronidazole
atenolol	metoprolol
azithromycin	nadolol
caffeine, dietary ingestion	nifedipine
cefaclor	nizatidine
co-trimoxazole (trimethoprim and sulfamethoxazole)	norfloxacin
co-trimoxazole (trimethoprim and sulfamethoxazole)	ofloxacin
diltiazem	omeprazole
dirithromycin	prednisone, prednisolone
enflurane	ranitidine
famotidine	rifabutin
felodipine	roxithromycin
finasteride	Sorbitol (purgative doses do not inhibit
hydrocortisone	theophylline absorption)
isoflurane	sucralfate
isoniazid	terbutaline, systemic
isradipine	terfenadine
influenza vaccine	tetracycline
ketoconazole	tocainide
lomefloxacin

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Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)	VIAGRA 25 mg
Supine	7.4 (-0.9, 15.7)
Standing	6.0 (-0.8, 12.8)

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Factors	Dosage Adjustments for Aripiprazole
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
Known CYP2D6 Poor Metabolizersand strong CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors	Administer half of usual dose
Strong CYP2D6 and CYP3A4inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double usual dose over 1 to 2 weeks

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Table 1: Clinically Significant Drug Interactions with Morphine Sulfate Injection, (Auto-Injector)
Benzodiazepines and other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:	If concomitant use is warranted, carefully observe the patient during treatment initiation. Discontinue Morphine Sulfate Injection, (Auto-Injector) if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.6)].
Intervention:	Do not use Morphine Sulfate Injection, (Auto-Injector) in patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses of other opioids (such as oxycodone, hydrocodone, oxymorphone, hydrocodone, or buprenorphine) to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of Morphine Sulfate Injection, (Auto-Injector) and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Morphine sulfate may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the frequency of injections of Morphine Sulfate Injection, (Auto-Injector) and/or decrease the dose of the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when Morphine Sulfate Injection, (Auto-Injector) is used concomitantly with anticholinergic drugs.

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Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs that Interfere with Hemostasis
Clinical Impact :	Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention :	Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see WARNINGS AND PRECAUTIONS ( 5 . 11 )].
Aspirin
Clinical Impact :	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see WARNINGS AND PRECAUTIONS ( 5 . 2 )].
Intervention :	Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see WARNINGS AND PRECAUTIONS ( 5 . 11 )]. Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors , Angiotensin Receptor Blockers , or Beta - Blockers
Clinical Impact :	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention :	During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see WARNINGS AND PRECAUTIONS ( 5 . 6 )]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact :	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention :	During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see WARNINGS AND PRECAUTIONS ( 5 . 6 )].
Lithium
Clinical Impact :	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [ see CLINICAL PHARMACOLOGY ( 12 . 3 )].
Intervention :	During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact :	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention :	During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact :	Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention :	During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact :	Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see WARNINGS AND PRECAUTIONS ( 5 . 2 )].
Intervention :	The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact :	Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention :	During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( 7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( 7)
Phenytoin	Monitor phenytoin level ( 7)
Methotrexate	Monitor for methotrexate toxicity ( 7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine ( 7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin ( 7)

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Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
* The interaction between nevirapine and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.
Drug Name	Effect on Concentration of Nevirapine or Concomitant Drug	Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir*	↓ Atazanavir ↑ Nevirapine	Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir*	↓ Amprenavir ↑ Nevirapine	Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir*	↓ Amprenavir ↑ Nevirapine	No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir*	↓ Indinavir	The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir*	↓Lopinavir	Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra^® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir*	↓Nelfinavir M8 Metabolite ↓Nelfinavir C_min	The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/ritonavir	The interaction between nevirapine and saquinavir/ritonavir has not been evaluated	The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz*	↓ Efavirenz	The appropriate doses of these combinations with respect to safety and efficacy have not been established.
Delavirdine Etravirine Rilpivirine		Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.
Hepatitis C Antiviral Agents
Boceprevir	Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine.	Nevirapine and boceprevir should not be coadministered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy.
Telaprevir	Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir.	Nevirapine and telaprevir should not be coadministered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events.
Other Agents
Analgesics:
Methadone*	↓ Methadone	Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics:
Amiodarone, disopyramide, lidocaine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Antibiotics:
Clarithromycin*	↓ Clarithromycin ↑ 14-OH clarithromycin	Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Rifabutin*	↑ Rifabutin	Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin*	↓ Nevirapine	Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants: Carbamazepine, clonazepam, ethosuximide	Plasma concentrations of nevirapine and the anticonvulsant may be decreased.	Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals:
Fluconazole*	↑Nevirapine	Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Ketoconazole*	↓ Ketoconazole	Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Itraconazole	↓ Itraconazole	Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics: Warfarin	Plasma concentrations may be increased.	Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers: Diltiazem, nifedipine, verapamil	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Cancer chemotherapy: Cyclophosphamide	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Ergot alkaloids: Ergotamine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Motility agents: Cisapride	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Opiate agonists: Fentanyl	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Oral contraceptives:
Ethinyl estradiol and Norethindrone*	↓ Ethinyl estradiol ↓ Norethindrone	Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.

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Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and Ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [ see Contraindications ( 4.2) ]
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of Ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate. [See Warnings and Precautions ( 5.6).]
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions ( 5.10) and Use in Specific Populations ( 8.5)].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when Ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when Ciprofloxacin is co-administered with oral antidiabetic drugs. [See Adverse Reactions ( 6.1).]
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon Ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of Ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when Ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of Ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of Ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant Ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with Ciprofloxacin [see Warnings and Precautions ( 5.15)].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with Ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution Two-fold increase in exposure	Monitor for sildenafil toxicity ( see Pharmacokinetics 12.3 ).
Duloxetine	Avoid Use Five-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity.
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration. ( 2)].	Decrease Ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid	Use with caution (interferes with renal tubular secretion of Ciprofloxacin and increases Ciprofloxacin serum levels)	Potentiation of Ciprofloxacin toxicity may occur.

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Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
*Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	Cmax
Enzyme (CYP2D6) inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not Needed

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Table 13. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Table 7 Summary of AED Interactions with Oxcarbazepine
¹ nc denotes a mean change of less than 10%
² Pediatrics
³ Mean increase in adults at high oxcarbazepine doses
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Dose (mg/day)	Influence of Oxcarbazepineon AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400 to 2000	900	nc¹	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100 to 150	600 to 1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250 to 500	600 to 1800 > 1200 to 2400	nc^1,2 up to 40% increase3 [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400 to 2800	600 to 1800	nc¹	18% decrease [CI: 13% decrease, 40% decrease]

Table 3: Clinically Relevant Interactions Affecting Drugs Co-Administered with Omeprazole and Interaction with Diagnostics
Antiretrovirals
Clinical Impact:	The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
Intervention:	Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications (4)]. Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:	Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention:	Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact:	Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].
Intervention:	A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact:	Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)]. There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention:	Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6)].
Citalopram
Clinical Impact:	Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention:	Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:	Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].
Intervention:	Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:	Potential for increased exposure of phenytoin.
Intervention:	Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:	Increased exposure of diazepam [see Clinical Pharmacology (12.3)].
Intervention:	Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:	Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention:	Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:	Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:	Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)]. See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:	Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:	See Contraindications, Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact:	Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention:	Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:	Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10), Clinical Pharmacology (12.2)].
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:	Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact:	There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:	An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:	There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:	Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.

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Table 6 Clinically Important Drug Interactions
Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Tricyclic antidepressants	Increase blood pressure and may counteract clonidine’s hypotensive effects	Monitor blood pressure and adjust as needed
Antihypertensive drugs	Potentiate clonidine’s hypotensive effects	Monitor blood pressure and adjust as needed
CNS depressants	Potentiate sedating effects	Avoid use
Drugs that affect sinus node function or AV node conduction (e.g., digitalis, calcium channel blockers, beta blockers)	Potentiate bradycardia and risk of AV block	Avoid use

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Table 29: Clinically Important Drug Interactions with Latuda
Strong CYP3A4 Inhibitors
Clinical Impact:	Concomitant use of LATUDA with strong CYP3A4 inhibitors increased the exposure of lurasidone compared to the use of LATUDA alone [see Clinical Pharmacology (12.3)].
Intervention:	LATUDA should not be used concomitantly with strong CYP3A4 inhibitors [see Contraindications (4)].
Examples:	Ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil
Moderate CYP3A4 Inhibitors
Clinical Impact:	Concomitant use of LATUDA with moderate CYP3A4 inhibitors increased the exposure of lurasidone compared to the use of LATUDA alone [see Clinical Pharmacology (12.3)].
Intervention:	LATUDA dose should be reduced to half of the original level when used concomitantly with moderate inhibitors of CYP3A4 [see Dosage and Administration (2.6)].
Examples:	Diltiazem, atazanavir, erythromycin, fluconazole, verapamil
Strong CYP3A4 Inducers
Clinical Impact:	Concomitant use of LATUDA with strong CYP3A4 inducers decreased the exposure of lurasidone compared to the use of LATUDA alone [see Clinical Pharmacology (12.3)].
Intervention:	LATUDA should not be used concomitantly with strong CYP3A4 inhibitors [see Contraindications (4)].
Examples:	Rifampin, avasimibe, St. John's wort, phenytoin, carbamazepine
Moderate CYP3A4 Inducers
Clinical Impact:	Concomitant use of LATUDA with strong CYP3A4 inducers decreased the exposure of lurasidone compared to the use of LATUDA alone [see Clinical Pharmacology (12.3)].
Intervention:	LATUDA dose should be increased when used concomitantly with moderate inducers of CYP3A4 [see Dosage and Administration (2.6)].
Examples:	Bosentan, efavirenz, etravirine, modafinil, nafcillin

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Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs that Interfere with Hemostasis
Clinical Impact:	Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions (5.2)].
Intervention:	Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions (5.11)]. Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, or Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention:	During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see Warnings and Precautions (5.6)].
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [ see Clinical Pharmacology (12.3)].
Intervention:	During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions (5.2)].
Intervention:	The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.

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Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.8) ].
Benzodiazepines (e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.8) ].	Monitor sedation and blood pressure. Adjust dose accordingly.

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, Amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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Antiretrovirals
Clinical Impact:	The effect of PPI on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and nelfinavir) when used concomitantly with rabeprazole may reduce antiviral effect and promote the development of drug resistance. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with rabeprazole may increase toxicity. There are other antiretroviral drugs which do not result in clinically relevant interactions with rabeprazole.
Intervention:	Rilpivirine-containing products: Concomitant use with Rabeprazole Sodium Delayed-Release Tablets is contraindicated [see Contraindications (4)]. See prescribing information. Atazanavir: See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with Rabeprazole Sodium Delayed-Release Tablets. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir and monitor for potential saquinavir toxicities. Other antiretrovirals: See prescribing information.
Warfarin
Clinical Impact:	Increased INR and prothrombin time in patients receiving PPIs, including rabeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death [see Warnings and Precautions (5.2)].
Intervention:	Monitor INR and prothrombin time. Dose adjustment of warfarin may be needed to maintain target INR range. See prescribing information for warfarin.
Methotrexate
Clinical Impact:	Concomitant use of rabeprazole with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of methotrexate with PPIs have been conducted [see Warnings and Precautions (5.9)].
Intervention:	A temporary withdrawal of Rabeprazole Sodium Delayed-Release Tablets may be considered in some patients receiving high dose methotrexate administration.
Digoxin
Clinical Impact:	Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention:	Monitor digoxin concentrations. Dose adjustment of digoxin may be needed to maintain therapeutic drug concentrations. See prescribing information for digoxin.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole, itraconazole)
Clinical Impact:	Rabeprazole can reduce the absorption of drugs due to its effect on reducing intragastric acidity.
Intervention:	Mycophenolate mofetil (MMF): Co-administration of PPIs in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving PPIs and MMF. Use Rabeprazole Sodium Delayed-Release Tablets with caution in transplant patients receiving MMF. See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:	Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:	See Contraindications and Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, gemfibrozil, cyclosporine,danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.^*
albuterol, systemic and inhaled	diltiazem	medroxyprogesterone	roxithromycin
albuterol, systemic and inhaled	dirithromycin	methylprednisolone	Sorbitol (purgative doses do not inhibit theophylline absorption)
amoxicillin	enflurane	metronidazole
ampicillin, with or without sulbactam	famotidine	metoprolol
	felodipine	nadolol
	finasteride	nifedipine
atenolol	hydrocortisone	nizatidine	sucralfate
azithromycin	isoflurane	norfloxacin	terbutaline, systemic
caffeine, dietary ingestion	isoniazid	ofloxacin	terfenadine
caffeine, dietary ingestion	isradipine	omeprazole	tetracycline
cefaclor	influenza vaccine	prednisone, prednisolone	tocainide
co-trimoxazole (trimethoprim and sulfamethoxazole)	ketoconazole	prednisone, prednisolone
	lomefloxacin	ranitidine
	mebendazole	rifabutin
^* Refer to PRECAUTIONS, Drug Interactions for information regarding table.

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Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name:

Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, Posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine,danazol	Contraindicated with simvastatin
Verapamil, diltiazem	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

Table name:

Table 4. Drug Interactions with PRIFTIN: Dosage Adjustment may be Necessary
Drug Class	Examples of Drugs Within Class
Antiarrhythmics	Disopyramide, mexiletine, quinidine, tocainide
Antibiotics	Chloramphenicol, clarithromycin, dapsone, doxycycline; Fluoroquinolones (such as ciprofloxacin)
Oral Anticoagulants	Warfarin
Anticonvulsants	Phenytoin
Antimalarials	Quinine
Azole Antifungals	Fluconazole, itraconazole, ketoconazole
Antipsychotics	Haloperidol
Barbiturates	Phenobarbital
Benzodiazepines	Diazepam
Beta-Blockers	Propanolol
Calcium Channel Blockers	Diltiazem, nifedipine, verapamil
Cardiac Glycoside Preparations	Digoxin
Corticosteroids	Prednisone
Fibrates	Clofibrate
Oral Hypoglycemics	Sulfonylureas (e.g., glyburide, glipizide)
Hormonal Contraceptives/ Progestins	Ethinyl estradiol, levonorgestrel
Immunosuppressants	Cyclosporine, tacrolimus
Methylxanthines	Theophylline
Narcotic analgesics	Methadone
Phophodiesterase-5 (PDE-5) Inhibitors	Sildenafil
Thyroid preparations	Levothyroxine
Tricyclic antidepressants	Amitriptyline, nortriptyline

Table name:

AED Coadministered	AED Concentration	Topiramate Concentration
^a = Plasma concentration increased 25% in some patients, generally those on a twice
a day dosing regimen of phenytoin.
^b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

Table name:

Table 13. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

Table name:

Table 8: Clinically Significant Drug Interactions with Clarithromycin
Drugs That Are Affected By Clarithromycin
Drug(s) with Pharmacokinetics Affected by Clarithromycin		Recommendation	Comments
Antiarrhythmics: Disopyramide Quinidine Dofetilide Amiodarone Sotalol Procainamide		Not Recommended	Disopyramide, Quinidine: There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs [see Warnings and Precautions (5.3)]. Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine. There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.
Digoxin		Use With Caution	Digoxin: Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are co-administered, inhibition of Pgp by clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range.
Oral Anticoagulants: Warfarin		Use With Caution	Oral anticoagulants: Spontaneous reports in the postmarketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously [see Warnings and Precautions (5.4)].
Antiepileptics: Carbamazepine		Use With Caution	Carbamazepine: Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered. Increased serum concentrations of carbamazepine were observed in clinical trials with clarithromycin. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with carbamazepine.
Antifungals: Itraconazole		Use With Caution	Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly (see also Itraconazole under “Drugs That Affect Clarithromycin” in the table below). Clarithromycin may increase the plasma concentrations of itraconazole. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions.
Fluconazole		No Dose Adjustment	Fluconazole: [see Pharmacokinetics (12.3)]
Anti-Gout Agents: Colchicine (in patients with renal or hepatic impairment) Colchicine (in patients with normal renal and hepatic function)		Contraindicated Use With Caution	Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. The dose of colchicine should be reduced when co-administered with clarithromycin in patients with normal renal and hepatic function [see Contraindications (4.4) and Warnings and Precautions (5.4)].
Antipsychotics: Pimozide Quetiapine		Contraindicated	Pimozide: [See Contraindications (4.2)] Quetiapine: Quetiapine is a substrate for CYP3A4, which is inhibited by clarithromycin. Co-administration with clarithromycin could result in increased quetiapine exposure and possible quetiapine related toxicities. There have been postmarketing reports of somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation during concomitant administration. Refer to quetiapine prescribing information for recommendations on dose reduction if co-administered with CYP3A4 inhibitors such as clarithromycin.
Antispasmodics: Tolterodine (patients deficient in CYP2D6 activity)		Use With Caution	Tolterodine: The primary route of metabolism for tolterodine is via. CYP2D6. However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via. CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when co-administered with clarithromycin.
Antivirals: Atazanavir		Use With Caution	Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)].
Saquinavir (in patients with decreased renal function)			Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction (see Saquinavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)].
Ritonavir Etravirine			Ritonavir, Etravirine: (see Ritonavir and Etravirine under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)].
Maraviroc			Maraviroc: Clarithromycin may result in increases in maraviroc exposures by inhibition of CYP3A metabolism. See Selzentry^® prescribing information for dose recommendation when given with strong CYP3A inhibitors such as clarithromycin.
Boceprevir (in patients with normal renal function) Didanosine		No Dose Adjustment	Boceprevir: Both clarithromycin and boceprevir are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when co-administered. No dose adjustments are necessary for patients with normal renal function (see Victrelis^® prescribing information).
Zidovudine			Zidovudine: Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Administration of clarithromycin and zidovudine should be separated by at least two hours [see Pharmacokinetics (12.3)].
Calcium Channel Blockers: Verapamil		Use With Caution	Verapamil: Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, [see Warnings and Precautions (5.4)].
Amlodipine Diltiazem			Amlodipine, Diltiazem: [See Warnings and Precautions (5.4)]
Nifedipine			Nifedipine: Nifedipine is a substrate for CYP3A. Clarithromycin and other macrolides are known to inhibit CYP3A. There is potential of CYP3A-mediated interaction between nifedipine and clarithromycin. Hypotension and peripheral edema were observed when clarithromycin was taken concomitantly with nifedipine [see Warnings and Precautions (5.4)].
Ergot Alkaloids: Ergotamine Dihydroergotamine		Contraindicated	Ergotamine, Dihydroergotamine: Postmarketing reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4.6)].
Gastroprokinetic Agents: Cisapride		Contraindicated	Cisapride: [See Contraindications (4.2)]
HMG-CoA Reductase Inhibitors: Lovastatin Simvastatin		Contraindicated	Lovastatin, Simvastatin, Atorvastatin, Pravastatin, Fluvastatin: [See Contraindications (4.5) and Warnings and Precautions (5.4)]
Atorvastatin Pravastatin		Use With Caution
Fluvastatin		No Dose Adjustment
Hypoglycemic Agents: Nateglinide Pioglitazone Repaglinide Rosiglitazone		Use With Caution	Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]
Insulin			Insulin: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]
Immunosuppressants: Cyclosporine		Use With Caution	Cyclosporine: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine.
Tacrolimus			Tacrolimus: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with tacrolimus.
Phosphodiesterase inhibitors: Sildenafil Tadalafil Vardenafil		Use With Caution	Sildenafil, Tadalafil, Vardenafil: Each of these phosphodiesterase inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant administration of clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil, or vardenafil will result in increased exposure of these phosphodiesterase inhibitors. Co-administration of these phosphodiesterase inhibitors with clarithromycin is not recommended. Increased systemic exposure of these drugs may occur with clarithromycin; reduction of dosage for phosphodiesterase inhibitors should be considered (see their respective prescribing information).
Proton Pump Inhibitors: Omeprazole		No Dose Adjustment	Omeprazole: The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when coadministered with clarithromycin as a result of increased omeprazole exposures [see Pharmacokinetics (12.3)] (see also Omeprazole under “Drugs That Affect Clarithromycin” in the table below).
Xanthine Derivatives: Theophylline		Use With Caution	Theophylline: Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations [see Pharmacokinetics (12.3)]. Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range.
Triazolobenzodiazepines and Other Related Benzodiazepines: Midazolam		Use With Caution	Midazolam: When oral midazolam is co-administered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated [see Warnings and Precautions (5.4) and Pharmacokinetics (12.3)].
Alprazolam Triazolam			Triazolam, Alprazolam: Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is co-administered with clarithromycin. There have been postmarketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested. In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines.
Temazepam Nitrazepam Lorazepam		No Dose Adjustment	Temazepam, Nitrazepam, Lorazepam: For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.
Cytochrome P450 Inducers: Rifabutin		Use With Caution	Rifabutin: Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis (see Rifabutin under “Drugs That Affect Clarithromycin” in the table below).
Other Drugs Metabolized by CYP3A: Alfentanil Bromocriptine Cilostazol Methylprednisole Vinblastine Phenobarbital St. John’s Wort		Use With Caution	There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort.
Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A:
Hexobarbital Phenytoin Valproate		Use With Caution	There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.
Drugs that Affect Clarithromycin
Drug(s) that Affect the Pharmacokinetics of Clarithromycin	Recommendation		Comments
Antifungals: Itraconazole	Use With Caution		Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions (see also Itraconazole under “Drugs That Are Affected By Clarithromycin” in the table above).
Antivirals: Atazanavir	Use With Caution		Atazanavir: When clarithromycin is co-administered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology (12.3)]. Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.
Ritonavir (in patients with decreased renal function)			Ritonavir: Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with ritonavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium [see Pharmacokinetics (12.3)]. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.
Saquinavir (in patients with decreased renal function)			Saquinavir: When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (refer to ritonavir above) [see Pharmacokinetics (12.3)].
Etravirine			Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.
Saquinavir (in patients with normal renal function) Ritonavir (in patients with normal renal function)	No Dose Adjustment
Proton Pump Inhibitors: Omeprazole	Use With Caution		Omeprazole: Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole [see Pharmacokinetics (12.3)].
Miscellaneous Cytochrome P450 Inducers: Efavirenz Nevirapine Rifampicin Rifabutin Rifapentine	Use With Caution		Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are Affected By Clarithromycin” in the table above).

Table name:

AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxideIs not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

Table name:

Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

Table name:

Specific Drugs Reported
also: other medications affecting blood elements which may modify hemostasis dietary deficiencies prolonged hot weather unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported.
acetaminophen alcohol† allopurinol aminosalicylic acid amiodarone HCl argatroban aspirin atenolol atorvastatin† azithromycin bivalirudin capecitabine cefamandole cefazolin cefoperazone cefotetan cefoxitin ceftriaxone celecoxib cerivastatin chenodiol chloramphenicol chloral hydrate† chlorpropamide cholestyramine† cimetidine ciprofloxacin cisapride clarithromycin clofibrate cyclophosphamide† danazol dextran dextrothyroxine diazoxide	diclofenac dicumarol diflunisal disulfiram doxycycline erythromycin esomeprazole ethacrynic acid ezetimibe fenofibrate fenoprofen fluconazole fluorouracil fluoxetine flutamide fluvastatin fluvoxamine gefitinib gemifibrozil glucagon halothane heparin ibuprofen ifosfamide indomethacin influenza virus vaccine itraconazole ketoprofen ketorolac lansoprazole lepirudin levamisole levofloxacin levothyroxine liothyronine	lovastatin mefenamic acid methimazole† methyldopa methylphenidate methylsalicylate ointment (topical) metronidazole miconazole (intravaginal, oral, systemic) moricizine hydrochloride† nalidixic acid naproxen neomycin norfloxacin ofloxacin olsalazine omeprazole oxandrolone oxaprozin oxymetholone pantoprazole paroxetine penicillin G, intravenous pentoxifylline phenylbutazone phenytoin† piperacillin piroxicam pravastatin† prednisone† propafenone	propoxyphene propranolol propylthiouracil† quinidine quinine rabeprazole ranitidine† rofecoxib sertraline simvastatin stanozolol streptokinase sulfamethizole sulfamethoxazole sulfinpyrazone sulfisoxazole sulindac tamoxifen tetracycline thyroid ticarcillin ticlopidine tissue plasminogen activator (t-PA) tolbutamide tramadol trimethoprim/ sulfamethoxazole urokinase valdecoxib valproate vitamin E warfarin overdose zafirlukast zileuton

Table name:

Table 8: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.6)] .
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were coadministered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported . Monitor blood glucose when ciprofloxacin is coadministered with oral antidiabetic drugs [see Adverse Reactions (6.1)] .
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is coadministered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after coadministration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after coadministration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution 2-fold increase in exposure	Monitor for sildenafil toxicity [see Pharmacokinetics (12.3)] .
Duloxetine	Avoid Use 5-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx ^®‡ (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2)].	Decrease ciprofloxacin absorption, resulting in lower serum and urine levels.
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

Table name:

AED Co - administered	AED Concentration	Topiramate Concentration
^a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
^b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
Phenytoin	NC or 25% increase ^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide ^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Table 5: Clarithromycin Tissue Concentrations 2 hours after Dose¹
	¹Mean ± (μg/g)
Tissue	Clarithromycin	Clarithromycin + Omeprazole
Antrum	10.48 ± 2.01 (n = 5)	19.96 ± 4.71 (n = 5)
Fundus	20.81 ± 7.64 (n = 5)	24.25 ± 6.37 (n = 5)
Mucus	4.15 ± 7.74 (n = 4)	39.29 ± 32.79 (n = 4)

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Table 8: Clinically Significant Drug Interactions with Clarithromycin
Drugs That Are Affected By Clarithromycin
Drug(s) with Pharmacokinetics Affected by Clarithromycin	Recommendation	Comments
Antiarrhythmics:
Disopyramide Quinidine Dofetilide Amiodarone Sotalol Procainamide	Not Recommended	Disopyramide, Quinidine: There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs [see Warnings and Precautions (5.3)]. Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine. There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.
Digoxin	Use With Caution	Digoxin: Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are co-administered, inhibition of Pgp by clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range.
Oral Anticoagulants:
Warfarin	Use With Caution	Oral anticoagulants: Spontaneous reports in the postmarketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously [see Warnings and Precautions (5.4)].
Antiepileptics:
Carbamazepine	Use With Caution	Carbamazepine: Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered. Increased serum concentrations of carbamazepine were observed in clinical trials with clarithromycin. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with carbamazepine.
Antifungals:
Itraconazole	Use With Caution	Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly (see also Itraconazole under “Drugs That Affect Clarithromycin” in the table below). Clarithromycin may increase the plasma concentrations of itraconazole. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions.
Fluconazole	No Dose Adjustment	Fluconazole: [see Pharmacokinetics (12.3)]
Anti-Gout Agents:
Colchicine (in patients with renal or hepatic impairment) Colchicine (in patients with normal renal and hepatic function)	Contraindicated Use With Caution	Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. The dose of colchicine should be reduced when co-administered with clarithromycin in patients with normal renal and hepatic function [see Contraindications (4.4) and Warnings and Precautions (5.4)].
Antipsychotics:
Pimozide	Contraindicated	Pimozide: [See Contraindications (4.2)]
Quetiapine		Quetiapine: Quetiapine is a substrate for CYP3A4, which is inhibited by clarithromycin. Co-administration with clarithromycin could result in increased quetiapine exposure and possible quetiapine related toxicities. There have been postmarketing reports of somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation during concomitant administration. Refer to quetiapine prescribing information for recommendations on dose reduction if co-administered with CYP3A4 inhibitors such as clarithromycin.
Antispasmodics:
Tolterodine (patients deficient in CYP2D6 activity)	Use With Caution	Tolterodine: The primary route of metabolism for tolterodine is via CYP2D6. However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when co-administered with clarithromycin.
Antivirals:
Atazanavir	Use With Caution	Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)].
Saquinavir (in patients with decreased renal function)		Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction (see Saquinavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)].
Ritonavir Etravirine		Ritonavir, Etravirine: (see Ritonavir and Etravirine under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)].
Maraviroc		Maraviroc: Clarithromycin may result in increases in maraviroc exposures by inhibition of CYP3A metabolism. See Selzentry^® prescribing information for dose recommendation when given with strong CYP3A inhibitors such as clarithromycin.
Boceprevir (in patients with normal renal function) Didanosine	No Dose Adjustment	Boceprevir: Both clarithromycin and boceprevir are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when co-administered. No dose adjustments are necessary for patients with normal renal function (see Victrelis^® prescribing information).
Zidovudine		Zidovudine: Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Administration of clarithromycin and zidovudine should be separated by at least two hours [see Pharmacokinetics (12.3)]. The impact of co-administration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated.
Calcium Channel Blockers:
Verapamil	Use With Caution	Verapamil: Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, [see Warnings and Precautions (5.4)].
Amlodipine Diltiazem		Amlodipine, Diltiazem: [See Warnings and Precautions (5.4)]
Nifedipine		Nifedipine: Nifedipine is a substrate for CYP3A. Clarithromycin and other macrolides are known to inhibit CYP3A. There is potential of CYP3A-mediated interaction between nifedipine and clarithromycin. Hypotension and peripheral edema were observed when clarithromycin was taken concomitantly with nifedipine [see Warnings and Precautions (5.4)].
Ergot Alkaloids:
Ergotamine Dihydroergotamine	Contraindicated	Ergotamine, Dihydroergotamine: Postmarketing reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4.6)].
Gastroprokinetic Agents:
Cisapride	Contraindicated	Cisapride: [See Contraindications (4.2)]
HMG-CoA Reductase Inhibitors:
Lovastatin Simvastatin	Contraindicated	Lovastatin, Simvastatin, Atorvastatin, Pravastatin, Fluvastatin: [See Contraindications (4.5) and Warnings and Precautions (5.4)]
Atorvastatin Pravastatin	Use With Caution
Fluvastatin	No Dose Adjustment
Hypoglycemic Agents:
Nateglinide Pioglitazone Repaglinide Rosiglitazone	Use With Caution	Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]
Insulin		Insulin: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]
Immunosuppressants:
Cyclosporine	Use With Caution	Cyclosporine: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine.
Tacrolimus		Tacrolimus: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with tacrolimus.
Phosphodiesterase inhibitors:
Sildenafil Tadalafil Vardenafil	Use With Caution	Sildenafil, Tadalafil, Vardenafil: Each of these phosphodiesterase inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant administration of clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil, or vardenafil will result in increased exposure of these phosphodiesterase inhibitors. Co-administration of these phosphodiesterase inhibitors with clarithromycin is not recommended. Increased systemic exposure of these drugs may occur with clarithromycin; reduction of dosage for phosphodiesterase inhibitors should be considered (see their respective prescribing information).
Proton Pump Inhibitors:
Omeprazole	No Dose Adjustment	Omeprazole: The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when coadministered with clarithromycin as a result of increased omeprazole exposures [see Pharmacokinetics (12.3)] (see also Omeprazole under “Drugs That Affect Clarithromycin” in the table below).
Xanthine Derivatives:
Theophylline	Use With Caution	Theophylline: Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations [see Pharmacokinetics (12.3)]. Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range.
Triazolobenzodiazepines and Other Related Benzodiazepines:
Midazolam	Use With Caution	Midazolam: When oral midazolam is co-administered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated [see Warnings and Precautions (5.4) and Pharmacokinetics (12.3)].
Alprazolam Triazolam		Triazolam, Alprazolam: Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is co-administered with clarithromycin. There have been postmarketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested. In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines.
Temazepam Nitrazepam Lorazepam	No Dose Adjustment	Temazepam, Nitrazepam, Lorazepam: For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.
Cytochrome P450 Inducers:
Rifabutin	Use With Caution	Rifabutin: Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis (see Rifabutin under “Drugs That Affect Clarithromycin” in the table below).
Other Drugs Metabolized by CYP3A:
Alfentanil Bromocriptine Cilostazol Methylprednisole Vinblastine Phenobarbital St. John’s Wort	Use With Caution	There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort.
Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A:
Hexobarbital Phenytoin Valproate	Use With Caution	There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.
Drugs that Affect Clarithromycin
Drug(s) that Affect the Pharmacokinetics of Clarithromycin	Recommendation	Comments
Antifungals:
Itraconazole	Use With Caution	Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions (see also Itraconazole under “Drugs That Are Affected By Clarithromycin” in the table above).
Antivirals:
Atazanavir	Use With Caution	Atazanavir: When clarithromycin is co-administered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology (12.3)]. Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.
Ritonavir (in patients with decreased renal function)		Ritonavir: Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with ritonavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium [see Pharmacokinetics (12.3)]. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.
Saquinavir (in patients with decreased renal function)		Saquinavir: When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (refer to ritonavir above) [see Pharmacokinetics (12.3)].
Etravirine		Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.
Saquinavir (in patients with normal renal function)	No Dose Adjustment
Ritonavir (in patients with normal renal function)
Proton Pump Inhibitors:
Omeprazole	Use With Caution	Omeprazole: Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole [see Pharmacokinetics (12.3)].
Miscellaneous Cytochrome P450 Inducers:
Efavirenz Nevirapine Rifampicin Rifabutin Rifapentine	Use With Caution	Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are Affected By Clarithromycin” in the table above).

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Drugs that Affect Renal Function	A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics	Dofetilide	Concomitant administration with digoxin was associated with a higher rate of Torsades de pointes.
	Sotalol	Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
	Dronedarone	Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog	Teriparatide	Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement	Thyroid	Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics	Epinephrine Norepinephrine Dopamine	Can increase the risk of cardiac arrhythmias.
Neuromuscular Blocking Agents	Succinylcholine	May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements	Calcium	If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers		Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.

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Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

Table name:

DRUG	DESCRIPTION OF INTERACTION
Corticosteroids	Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents	Increases plasma salicylate level.
Alkalizing Agents	Decreased plasma salicylate levels.

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I. Due to the competition of salicylate with other drugs for binding to serum albumin the following drug interactions may occur:
DRUG	DESCRIPTION OF INTERACTION
Sulfonylureas	Hypoglycemia potentiated.
Methotrexate	Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants	Increased bleeding.
II. Drugs changing salicylate levels by altering renal tubular reabsorption:
DRUG	DESCRIPTION OF INTERACTION
Corticosteroids	Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents	Increases plasma salicylate levels.
Alkanizing Agents	Decreased plasma salicylate levels.
III. Drugs with complicated interactions with salicylates:
DRUG	DESCRIPTION OF INTERACTION
Heparin	Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients.
Pyrazinamide	Inhibits pyrazinamide-induced hyperuricemia.
Uricosuric Agents	Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.
The following alterations of laboratory tests have been reported during salicylate therapy:
LABORATORY TESTS	EFFECT OF SALICYLATES
Thyroid Function	Decreased PBI; increased t₃ uptake.
Urinary Sugar	False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.).
5-Hydroxyindole acetic acid	False negative with fluorometric test.
Acetone ketone bodies	False positive FeCI₃ in Gerhardt reaction; red color persists with boiling.
17-OH corticosteroids	False reduced values with >4.8g q.d. salicylate.
Vanilmandelic acid	False reduced values.
Uric Acid	May increase or decrease depending on dose.
Prothrombin	Decreased levels; slightly increased prothrombin time.

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Figure 5: Mean Standing Systolic Blood Pressure Change from Baseline

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
↓= Decreased (induces lamotrigine glucuronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ? = Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine concentrations approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine and carbamazepine epoxide	? carbamazepine epoxide	May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Factors	Dosage Adjustments for Aripiprazole
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
Known CYP2D6 Poor Metabolizersand strong CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors	Administer half of usual dose
Strong CYP2D6 and CYP3A4inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double usual dose over 1 to 2 weeks

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Table 13. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation). ↑ = Increased (inhibits lamotrigine glucuronidation). ? = Conflicting data.
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., Itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily*
Grapefruit juice	Avoid grapefruit juice

Table name:

AED Co - administered	AED Concentration	Topiramate Concentration
^a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
^b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
Phenytoin	NC or 25% increase ^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide ^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine concentrations approximately 50% Decrease in levonorgestrel component by 19%
Carbamazepine and carbamazepine epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%
Carbamazepine and carbamazepine epoxide	? carbamazepine epoxide	May increase CBZ epoxide levels
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%
Valproate	↑lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold
Valproate	? valproate	There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Table 14: Clinically Important Drug Interactions: Effect of other Drugs on INTUNIV^®
Concomitant Drug Name or Drug Class	Clinical Rationale and Magnitude of Drug Interaction	Clinical Recommendation
Strong and moderate CYP3A4 inhibitors, e.g., ketoconazole, fluconazole	Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in an increase in exposure	Consider dose reduction [see Dosage and administration (2.7)]
Strong and moderate CYP3A4 inducers, e.g., rifampin, efavirenz	Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in a decrease in exposure	Consider dose increase [see Dosage and administration (2.7)]

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Specific Drugs Reported
also: other medications affecting blood elements which may modify hemostasis dietary deficiencies prolonged hot weather unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported.
acetaminophen alcohol† allopurinol aminosalicylic acid amiodarone HCl argatroban aspirin atenolol atorvastatin† azithromycin bivalirudin capecitabine cefamandole cefazolin cefoperazone cefotetan cefoxitin ceftriaxone celecoxib cerivastatin chenodiol chloramphenicol chloral hydrate† chlorpropamide cholestyramine† cimetidine ciprofloxacin cisapride clarithromycin clofibrate cyclophosphamide† danazol dextran dextrothyroxine diazoxide	diclofenac dicumarol diflunisal disulfiram doxycycline erythromycin esomeprazole ethacrynic acid ezetimibe fenofibrate fenoprofen fluconazole fluorouracil fluoxetine flutamide fluvastatin fluvoxamine gefitinib gemifibrozil glucagon halothane heparin ibuprofen ifosfamide indomethacin influenza virus vaccine itraconazole ketoprofen ketorolac lansoprazole lepirudin levamisole levofloxacin levothyroxine liothyronine	lovastatin mefenamic acid methimazole† methyldopa methylphenidate methylsalicylate ointment (topical) metronidazole miconazole (intravaginal, oral, systemic) moricizine hydrochloride† nalidixic acid naproxen neomycin norfloxacin ofloxacin olsalazine omeprazole oxandrolone oxaprozin oxymetholone pantoprazole paroxetine penicillin G, intravenous pentoxifylline phenylbutazone phenytoin† piperacillin piroxicam pravastatin† prednisone† propafenone	propoxyphene propranolol propylthiouracil† quinidine quinine rabeprazole ranitidine† rofecoxib sertraline simvastatin stanozolol streptokinase sulfamethizole sulfamethoxazole sulfinpyrazone sulfisoxazole sulindac tamoxifen tetracycline thyroid ticarcillin ticlopidine tissue plasminogen activator (t-PA) tolbutamide tramadol trimethoprim/ sulfamethoxazole urokinase valdecoxib valproate vitamin E warfarin overdose zafirlukast zileuton

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AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase= Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide= Is not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

Table name:

Drug	Effect
Phenylephrine with prior administration of monoamine oxidase inhibitors (MAOI).	Cardiac pressor response potentiated. May cause acute hypertensive crisis.
Phenylephrine with tricyclic antidepressants.	Pressor response increased.
Phenylephrine with ergot alkaloids.	Excessive rise in blood pressure.
Phenylephrine with bronchodilator sympathomimetic agents and with epinephrine or other sympathomimetics.	Tachycardia or other arrhythmias may occur.
Phenylephrine with prior administration of propranolol or other β-adrenergic blockers.	Cardiostimulating effects blocked.
Phenylephrine with atropine sulfate.	Reflex bradycardia blocked; pressor response enhanced.
Phenylephrine with prior administration of phentolamine or other α-adrenergic blockers.	Pressor response decreased.
Phenylephrine with diet preparations, such as amphetamines or phenylpropanolamine.	Synergistic adrenergic response.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
* Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing.
	20 mg/day	4 mg/day	1.6	-	Do not exceed 8 mg/day
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed

Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

Table name: FactorsDosage Adjustments for AripiprazoleAdminister half of usual doseAdminister a quarter of usual doseStrong CYP2D6 or CYP3A4 inhibitorsAdminister half of usual doseStrong CYP2D6 and CYP3A4 inhibitorsAdminister a quarter of usual doseStrong CYP3A4 inducersDouble usual dose over 1 to 2 weeks




Known CYP2D6 Poor Metabolizers
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors

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Table 10 Drugs That Should Not Be Coadministered With VIRACEPT
Drug Class: Drug Name	Clinical Comment

Alpha 1-adrenoreceptor antagonist: alfuzosin	Potentially increased alfuzosin concentrations can result in hypotension.
Antiarrhythmics: amiodarone, quinidine	CONTRAINDICATED due to potential for serious and/or life threatening reactions such as cardiac arrhythmias.
Antimycobacterial: rifampin	May lead to loss of virologic response and possible resistance to VIRACEPT or other coadministered antiretroviral agents.
Ergot Derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine	CONTRAINDICATED due to potential for serious and/or life threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
Herbal Products: St. John's wort (hypericum perforatum)	May lead to loss of virologic response and possible resistance to VIRACEPT or other coadministered antiretroviral agents.
HMG-CoA Reductase Inhibitors: lovastatin, simvastatin	Potential for serious reactions such as risk of myopathy including rhabdomyolysis.
Neuroleptic: pimozide	CONTRAINDICATED due to potential for serious and/or life threatening reactions such as cardiac arrhythmias.
PDE5 inhibitor: sildenafil (REVATIO) [for treatment of pulmonary arterial hypertension]	A safe and effective dose has not been established when used with VIRACEPT. There is increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, prolonged erection, and syncope).
Proton Pump Inhibitors	Omeprazole decreases the plasma concentrations of nelfinavir. Concomitant use of proton pump inhibitors and VIRACEPT may lead to a loss of virologic response and development of resistance.
Sedative/Hypnotics: midazolam, triazolam	CONTRAINDICATED due to potential for serious and/or life threatening reactions such as prolonged or increased sedation or respiratory depression.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 4. Mean (95% C.I.) maximal change in baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in healthy volunteers on daily alpha-blocker therapy
		Dosing of Vardenafil and Alpha-Blocker Separated by 6 Hours		Simultaneous dosing of Vardenafil and Alpha-Blocker
Alpha-Blocker		Vardenafil 10 mg Placebo-Subtracted	Vardenafil 20 mg Placebo-Subtracted	Vardenafil 10 mg Placebo-Subtracted	Vardenafil 20 mg Placebo-Subtracted
Terazosin 10 mg daily	Standing SBP	-7 (-10, -3)	-11 (-14, -7)	-23 (-31, 16) Due to the sample size, confidence intervals may not be an accurate measure for these data. These values represent the range for the difference.	-14 (-33, 11)
Terazosin 10 mg daily	Supine SBP	-5 (-8, -2)	-7 (-11, -4)	-7 (-25, 19)	-7 (-31, 22)
Tamsulosin 0.4 mg daily	Standing SBP	-4 (-8, -1)	-8 (-11, -4)	-8 (-14, -2)	-8 (-14, -1)
	Supine SBP	-4 (-8, 0)	-7 (-11, -3)	-5 (-9, -2)	-3 (-7, 0)

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NA = Not available/reported
Digoxin concentrations increased greater than 50%
	Digoxin Serum Concentration Increase	Digoxin AUC Increase	Recommendations
Amiodarone	70%	NA	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
Captopril	58%	39%
Clarithromycin	NA	70%
Dronedarone	NA	150%
Gentamicin	129-212%	NA
Erythromycin	100%	NA
Itraconazole	80%	NA
Lapatinib	NA	180%
Propafenone	NA	60-270%
Quinidine	100%	NA
Ranolazine	50%	NA
Ritonavir	NA	86%
Telaprevir	50%	85%
Tetracycline	100%	NA
Verapamil	50-75%	NA
Digoxin concentrations increased less than 50%
Atorvastatin	22%	15%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
Carvedilol	16%	14%
Conivaptan	33%	43%
Diltiazem	20%	NA
Indomethacin	40%	NA
Nefazodone	27%	15%
Nifedipine	45%	NA
Propantheline	24%	24%
Quinine	NA	33%
Rabeprazole	29%	19%
Saquinavir	27%	49%
Spironolactone	25%	NA
Telmisartan	20-49%	NA
Ticagrelor	31%	28%
Tolvaptan	30%	20%
Trimethoprim	22-28%	NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate and sulfasalazine			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20-40% as necessary.

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Factors	Dosage Adjustments for ABILIFY
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors	Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double usual dose over 1 to 2 weeks

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Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Digoxin concentrations increased greater than 50%
	Digoxin Serum Concentration Increase	Digoxin AUC Increase	Recommendations
Amiodarone	70%	NA	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30% to 50% or by modifying the dosing frequency and continue monitoring.
Captopril	58%	39%
Clarithromycin	NA	70%
Dronedarone	NA	150%
Gentamicin	129 to 212%	NA
Erthromycin	100%	NA
Itraconazole	60%	NA
Lapatinib	NA	180%
Propafenone	NA	60 to 270 %
Quinidine	100%	NA
Ranolazine	50%	NA
Ritonavir	NA	86%
Telaprevir	50%	85%
Tetracycline	100%	NA
Verapamil	50 to 75%	NA
Digoxin concentrations increased less than 50%
Atorvastatin	22%	15%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15% to 30% or by modifying the dosing frequency and continue monitoring.
Carvedilol	16%	14%
Conivaptan	33%	43%
Diltiazem	20%	NA
Indomethacin	40%	NA
Nefazodone	27%	15%
Nifedipine	45%	NA
Propantheline	24%	24%
Quinine	NA	33%
Rabeprazole	29%	19%
Saquinavir	27%	49%
Spironolactone	25%	NA
Telmisartan	20 to 49%	NA
Ticagrelor	31%	28%
Tolvaptan	30%	20%
Trimethoprim	22 to28%	NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate, and sulfasalazine			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20 % to 40 % as necessary.

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Interacting Agent	Examples
Drugs whose efficacy is impaired by phenytoin
Azoles	Fluconazole, ketoconazole, itraconazole, posaconazole, voriconazole
Antineoplastic agents	Irinotecan, paclitaxel, teniposide
Delavirdine	Phenytoin can substantially reduce the concentrations of delavirdine. This can lead to loss of virologic response and possible resistance [see Contraindications (4)].
Neuromuscular blocking agents	Cisatracurium, pancuronium, rocuronium and vecuronium: resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents has occurred in patients chronically administered phenytoin. Whether or not phenytoin has the same effect on other non-depolarizing agents is unknown. Prevention or Management: Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher.
Warfarin	Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin
Other	Corticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D
Drugs whose level is decreased by phenytoin
Antiepileptic drugs^a	Carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine
Antilipidemic agents	Atorvastatin, fluvastatin, simvastatin
Antiviral agents	Efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir Fosamprenavir: phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir
Calcium channel blockers	Nifedipine, nimodipine, nisoldipine, verapamil
Other	Albendazole (decreases active metabolite), chlorpropamide, clozapine, cyclosporine, digoxin, folic acid, methadone, mexiletine, praziquantel, quetiapine

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Bleeding times
Clinical Impact:	Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention:	This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact:	The administration of naproxen may result in increased urinary values for 17 ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention:	Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact:	Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention:	This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.

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Drug	Description of Interaction
I. Due to the competition of salicylate with other drugs for binding to serum albumin the following drug interactions may occur:
Tolbutamide; Sulfonylureas	Hypoglycemia potentiated
Methotrexate	Decrease tubular reabsorption; clinical toxicity from methotrexate can result
Oral Anticoagulants	Increased bleeding
II. Drugs changing salicylate levels by altering renal tubular reabsorption:
Drug	Description of Interaction
Corticosteroids	Decreases plasma salicylate level; tapering doses of steroids may promote salicylism
Ammonium Sulfate	Increases plasma salicylate level
III. Drugs with complicated interactions with salicylates:
Drug	Description of Interaction
Heparin	Salicylate decreases platelet adhesivesness and interferes with hemostasis in heparin-treated patients
Pyrazinamide	Inhibits pyrazinamide-induced hyperuricemia
Uricosuric Agents	Effect of probenecid, sulfinpyrazone and phenylbutazone inhibited
The following alterations of laboratory tests have been reported during salicylate therapy⁶:
Laboratory Tests	Effect of Salicylates
Thyroid Function	Decreased PBI; increased T₃ uptake
Urinary Sugar	False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2 - 5 g qd)
5 Hydroxyindole Acetic Acid	False negative with fluorometric test
Acetone, Ketone Bodies	False positive FeCl₃ in Gerhardt reaction; red color persists with boiling
17-OH Corticosteroids	False reduced values with >4.8 g qd salicylate
Vanilmandelic Acid	False reduced values
Uric Acid	May increase or decrease depending on dose
Prothrombin	Decreased levels; slightly increased prothrombin time

Table name:

Antiretrovirals
Clinical Impact:	The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see C li n i cal P harmacology (12.3)] . Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see C l i n i cal P harmacology (12.3)] . There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
Intervention:	R il p i v i rine-containing products: Concomitant use with Omeprazole Delayed-Release Capsules is contraindicated [see C o ntraindications (4)]. A t azanavir: Avoid concomitant use with Omeprazole Delayed-Release Capsules. See prescribing information for atazanavir for dosing information. N elfinavir: Avoid concomitant use with Omeprazole Delayed-Release Capsules. See prescribing information for nelfinavir. S aquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:	Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention:	Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact:	Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see W arnings and Precautions (5.11)].
Intervention:	A temporary withdrawal of Omeprazole Delayed-Release Capsules may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact:	Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see C li n i cal P harmacology (12.3)] . There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention:	Avoid concomitant use with Omeprazole Delayed-Release Capsules. Consider use of alternative anti-platelet therapy [see W arnings and Precautions (5.6)].
Citalopram
Clinical Impact:	Increased exposure of citalopram leading to an increased risk of QT prolongation [ see C li n i cal Pharmacology (12.3)].
Intervention:	Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:	Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see C l i nical Pharmacology (12.3)].
Intervention:	Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:	Potential for increased exposure of phenytoin.
Intervention:	Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:	Increased exposure of diazepam [see C l i nical Pharmacology (12.3)].
Intervention:	Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:	Potential for increased exposure of digoxin [see C l i n i c al Pharmacology (12.3)].
Intervention:	Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
D rugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:	Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:	Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving Omeprazole Delayed-Release Capsules and MMF. Use Omeprazole Delayed-Release Capsules with caution in transplant patients receiving MMF [see C l i nical P harmacology (12.3)]. See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:	Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:	See Contraindications, Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact:	Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention:	Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:	Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see W arnings and Precautions (5.10) , C li n i cal P harmacology (12.2)].
Intervention:	Temporarily stop Omeprazole Delayed-Release Capsules treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:	Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:	Temporarily stop Omeprazole Delayed-Release Capsules treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see C li n i cal Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact:	There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:	An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:	There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:	Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with Omeprazole Delayed-Release Capsules.

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Inhibitors of CYP3A4
Clinical Impact:	The concomitant use of fentanyl transdermal system and CYP3A4 inhibitors can increase the plasma concentration of fentanyl, resulting in increased or prolonged opioid effects particularly when an inhibitor is added after a stable dose of fentanyl transdermal system is achieved [see Warnings and Precautions (5.5)]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the fentanyl transdermal system plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to fentanyl.
Intervention:	If concomitant use is necessary, consider dosage reduction of fentanyl transdermal system until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the fentanyl transdermal system dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir), grape fruit juice
CYP3A4 Inducers
Clinical Impact:	The concomitant use of fentanyl transdermal system and CYP3A4 inducers can decrease the plasma concentration of fentanyl [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to fentanyl [see Warnings and Precautions (5.5)]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the fentanyl plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention:	If concomitant use is necessary, consider increasing the fentanyl transdermal system dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider fentanyl transdermal system dosage reduction and monitor for signs of respiratory depression.
Examples:	Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.7)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions 5.10].
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue fentanyl transdermal system if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.10)] or opioid toxicity (e.g., respiratory depression, coma).
Intervention:	The use of fentanyl transdermal system is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of fentanyl transdermal system and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Fentanyl transdermal system may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of fentanyl transdermal system and/or the muscle relaxant as necessary.

Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when fentanyl transdermal system is used concomitantly with anticholinergic drugs.

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Table II. Clinically significant drug interactions with theophylline.Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
Drug	Type of Interaction	Effect Average effect on steady-state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine	Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.
Alcohol	A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours.	30% increase
Allopurinol	Decreases theophylline clearance at allopurinol doses ≥600 mg/day.	25% increase
Aminoglutethimide	Increases theophylline clearance by induction of microsomal enzyme activity.	25% decrease
Carbamazepine	Similar to aminoglutethimide.	30% decrease
Cimetidine	Decreases theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase
Ciprofloxacin	Similar to cimetidine.	40% increase
Clarithromycin	Similar to erythromycin.	25% increase
Diazepam	Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.	Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram	Decreases theophylline clearance by inhibiting hydroxylation and demethylation.	50% increase
Enoxacin	Similar to cimetidine.	300% increase
Ephedrine	Synergistic CNS effects	Increased frequency of nausea, nervousness, and insomnia.
Erythromycin	Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen	Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.	30% increase
Flurazepam	Similar to diazepam.	Similar to diazepam.
Fluvoxamine	Similar to cimetidine.	Similar to cimetidine.
Halothane	Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.	Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A	Decreases theophylline clearance.	100% increase
Isoproterenol (IV)	Increase theophylline clearance.	20% increase
Ketamine	Pharmacologic	May lower theophylline seizure threshold.
Lithium	Theophylline increases renal lithium clearance.	Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam	Similar to diazepam.	Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.	20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine	Similar to disulfiram.	80% increase
Midazolam	Similar to diazepam.	Similar to diazepam.
Moricizine	Increases theophylline clearance.	25% decrease
Pancuronium	Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.	Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline	Decreases theophylline clearance.	30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.	25% decrease after two weeks of concurrent PB.
Phenytoin	Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.	Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone	Decreases theophylline clearance and pharmacologic interaction.	40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and pharmacologic interaction.	100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin	Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.	20 to 40% decrease
Sulfinpyrazone	Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.	20% increase
Tacrine	Similar to cimetidine, also increases renal clearance of theophylline.	90% increase
Thiabendazole	Decreases theophylline clearance.	190% increase
Ticlopidine	Decreases theophylline clearance.	60% increase
Troleandomycin	Similar to erythromycin.	33 to 100% increase depending on troleandomycin dose.
Verapamil	Similar to disulfiram.	20% increase

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( , , , , , , ) 2.3 4 5.1 7.1 7.2 7.3 12.3
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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Drugs that Interfere with Hemostasis
Clinical Impact:	Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention:	Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, or Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention:	During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology (12.3)].
Intervention:	During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention:	The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.

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Table 6: Predicted Drug Interactions with Didanosine Delayed-Release Capsules
Drug or Drug Class	Effect	Clinical Comment
Drugs that may cause pancreatic toxicity	↑risk of pancreatitis	Use only with extreme caution.Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of didanosine delayed-release capsules is recommended [see Warnings and Precautions (5.1)].
Neurotoxic drugs	↑risk of neuropathy	Use with caution.[See Warnings and Precautions (5.6)].
↑ Indicates increase.

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Table 3: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Indinavir (See PRECAUTIONS, Table 9 for Recommended Alterations in Dose or Regimen)
Coadministered drug	Dose of Coadministered drug (mg)	Dose of CRIXIVAN (mg)	n	Ratio (with/without CRIXIVAN) of Coadministered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00
				C_max	AUC	C_min
All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
Clarithromycin	500 twice daily, 7 days	800 three times daily, 7 days	12	1.19 (1.02, 1.39)	1.47 (1.30, 1.65)	1.97 (1.58, 2.46) n=11
Efavirenz	200 once daily, 14 days	800 three times daily, 14 days	20	No significant change	No significant change	--
Ethinyl Estradiol (ORTHO-NOVUM 1/35)Registered trademark of Ortho Pharmaceutical Corporation.	35 mcg, 8 days	800 three times daily, 8 days	18	1.02 (0.96, 1.09)	1.22 (1.15, 1.30)	1.37 (1.24, 1.51)
Isoniazid	300 once daily in the morning, 8 days	800 three times daily, 8 days	11	1.34 (1.12, 1.60)	1.12 (1.03, 1.22)	1.00 (0.92, 1.08)
MethadoneStudy conducted in subjects on methadone maintenance.	20-60 once daily in the morning, 8 days	800 three times daily, 8 days	12	0.93 (0.84, 1.03)	0.96 (0.86, 1.06)	1.06 (0.94, 1.19)
Norethindrone (ORTHO-NOVUM 1/35)	1 mcg, 8 days	800 three times daily, 8 days	18	1.05 (0.95, 1.16)	1.26 (1.20, 1.31)	1.44 (1.32, 1.57)
Rifabutin 150 mg once daily in the morning, 11 days + indinavir compared to 300 mg once daily in the morning, 11 days alone	150 once daily in the morning, 10 days 300 once daily in the morning, 10 days	800 three times daily, 10 days 800 three times daily, 10 days	14 10	1.29 (1.05, 1.59) 2.34 (1.64, 3.35)	1.54 (1.33, 1.79) 2.73 (1.99, 3.77)	1.99 (1.71, 2.31) n=13 3.44 (2.65, 4.46) n=9
Ritonavir	100 twice daily, 14 days	800 twice daily, 14 days	10, 4Parallel group design; n for coadministered drug + indinavir, n for coadministered drug alone.	1.61 (1.13, 2.29)	1.72 (1.20, 2.48)	1.62 (0.93, 2.85)
	200 twice daily, 14 days	800 twice daily, 14 days	9, 5	1.19 (0.85, 1.66)	1.96 (1.39, 2.76)	4.71 (2.66, 8.33) n=9, 4
Saquinavir
Hard gel formulation	600 single dose	800 three times daily, 2 days	6	4.7 (2.7, 8.1)	6.0 (4.0, 9.1)	2.9 (1.7, 4.7)C_6hr
Soft gel formulation	800 single dose	800 three times daily, 2 days	6	6.5 (4.7, 9.1)	7.2 (4.3, 11.9)	5.5 (2.2, 14.1)
Soft gel formulation	1200 single dose	800 three times daily, 2 days	6	4.0 (2.7, 5.9)	4.6 (3.2, 6.7)	5.5 (3.7, 8.3)
Sildenafil	25 single dose	800 three times daily	6	See text below for discussion of interaction.
StavudineStudy conducted in HIV-positive subjects.	40 twice daily, 7 days	800 three times daily, 7 days	13	0.86 (0.73, 1.03)	1.21 (1.09, 1.33)	Not Done
Theophylline	250 single dose (on Days 1 and 7)	800 three times daily, 6 days (Days 2 to 7)	12, 4	0.88 (0.76, 1.03)	1.14 (1.04, 1.24)	1.13 (0.86, 1.49) n=7, 3
Trimethoprim/ Sulfamethoxazole
Trimethoprim	800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days	400 q6h, 7 days	12	1.18 (1.05, 1.32)	1.18 (1.05, 1.33)	1.18 (1.00, 1.39)
Trimethoprim/ Sulfamethoxazole
Sulfamethoxazole	800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days	400 q6h, 7 days	12	1.01 (0.95, 1.08)	1.05 (1.01, 1.09)	1.05 (0.97, 1.14)
Vardenafil	10 single dose	800 three times daily	18	See text below for discussion of interaction.
Zidovudine	200 three times daily, 7 days	1000 three times daily, 7 days	12	0.89 (0.73, 1.09)	1.17 (1.07, 1.29)	1.51 (0.71, 3.20) n=4
Zidovudine/ Lamivudine
Zidovudine	200/150 three times daily, 7 days	800 three times daily, 7 days	6, 7	1.23 (0.74, 2.03)	1.39 (1.02, 1.89)	1.08 (0.77, 1.50) n=5, 5
Zidovudine/ Lamivudine
Lamivudine	200/150 three times daily, 7 days	800 three times daily, 7 days	6, 7	0.73 (0.52, 1.02)	0.91 (0.66, 1.26)	0.88 (0.59, 1.33)

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Interacting Agents	Prescribing Recommendation
Strong CYP3A4 inhibitors (e.g,. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir nefazodone, cobicistatcontaining products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily*
Grapefruit juice	Avoid grapefruit juice

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Interacting Drug	Interaction
Multivalent cation – containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.12, 7.3)

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AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxideIs not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease






























Intervention:

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Table 9: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [See Clinical Pharmacology (12.3) for Magnitude of Interaction, Tables 12 and 13]
Concomitant Drug Class: Drug Name	Effect on Concentration of Darunavir or Concomitant Drug	Clinical Comment
HIV-1-Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
didanosine	↔ darunavir ↔ didanosine	Didanosine should be administered one hour before or two hours after PREZISTA/ritonavir (which are administered with food).
HIV-1-Antiviral Agents: HIV-Protease Inhibitors (PIs)
indinavir (The reference regimen for indinavir was indinavir/ritonavir 800/100 mg twice daily.)	↑ darunavir ↑ indinavir	The appropriate dose of indinavir in combination with PREZISTA/ritonavir has not been established.
lopinavir/ritonavir	↓ darunavir ↔ lopinavir	Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer lopinavir/ritonavir and PREZISTA, with or without ritonavir.
saquinavir	↓ darunavir ↔ saquinavir	Appropriate doses of the combination have not been established. Hence, it is not recommended to co-administer saquinavir and PREZISTA, with or without ritonavir.
HIV-1-Antiviral Agents: CCR5 co-receptor antagonists
maraviroc	↑ maraviroc	Maraviroc concentrations are increased when co-administered with PREZISTA/ritonavir. When used in combination with PREZISTA/ritonavir, the dose of maraviroc should be 150 mg twice daily.
Other Agents
Antiarrhythmics: bepridil, lidocaine (systemic), quinidine, amiodarone, flecainide, propafenone	↑ antiarrhythmics	Concentrations of these drugs may be increased when co-administered with PREZISTA/ritonavir. Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when co-administered with PREZISTA/ritonavir.
digoxin	↑ digoxin	The lowest dose of digoxin should initially be prescribed. The serum digoxin concentrations should be monitored and used for titration of digoxin dose to obtain the desired clinical effect.
Anticoagulant: warfarin	↓ warfarin ↔ darunavir	Warfarin concentrations are decreased when co-administered with PREZISTA/ritonavir. It is recommended that the international normalized ratio (INR) be monitored when warfarin is combined with PREZISTA/ritonavir.
Anticonvulsant: carbamazepine	↔ darunavir ↑ carbamazepine	The dose of either darunavir/ritonavir or carbamazepine does not need to be adjusted when initiating co-administration with darunavir/ritonavir and carbamazepine. Clinical monitoring of carbamazepine concentrations and its dose titration is recommended to achieve the desired clinical response.
Anticonvulsant: phenobarbital, phenytoin	↔ darunavir ↓ phenytoin ↓ phenobarbital	Co-administration of PREZISTA/ritonavir may cause a decrease in the steady-state concentrations of phenytoin and phenobarbital. Phenytoin and phenobarbital levels should be monitored when co-administering with PREZISTA/ritonavir.
Antidepressant: trazodone, desipramine	↑ trazodone ↑ desipramine	Concomitant use of trazodone or desipramine and PREZISTA/ritonavir may increase plasma concentrations of trazodone or desipramine which may lead to adverse events such as nausea, dizziness, hypotension and syncope. If trazodone or desipramine is used with PREZISTA/ritonavir, the combination should be used with caution, and a lower dose of trazodone or desipramine should be considered.
Anti-infective: clarithromycin	↔ darunavir ↑ clarithromycin	No dose adjustment of the combination is required for patients with normal renal function. For patients with renal impairment, the following dose adjustments should be considered: For subjects with CLcr of 30–60 mL/min, the dose of clarithromycin should be reduced by 50%. For subjects with CLcr of < 30 mL/min, the dose of clarithromycin should be reduced by 75%.
Antifungals: ketoconazole, itraconazole, voriconazole	↑ ketoconazole ↑ darunavir ↑ itraconazole (not studied) ↓ voriconazole (not studied)	Ketoconazole and itraconazole are potent inhibitors as well as substrates of CYP3A. Concomitant systemic use of ketoconazole, itraconazole, and darunavir/ritonavir may increase plasma concentration of darunavir.
		Plasma concentrations of ketoconazole or itraconazole may be increased in the presence of darunavir/ritonavir. When co-administration is required, the daily dose of ketoconazole or itraconazole should not exceed 200 mg.
		Plasma concentrations of voriconazole may be decreased in the presence of darunavir/ritonavir. Voriconazole should not be administered to patients receiving darunavir/ritonavir unless an assessment of the benefit/risk ratio justifies the use of voriconazole.
Anti-gout: colchicine	↑ colchicine	Treatment of gout-flares – co-administration of colchicine in patients on PREZISTA/ritonavir: 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days. Prophylaxis of gout-flares – co-administration of colchicine in patients on PREZISTA/ritonavir: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever – co-administration of colchicine in patients on PREZISTA/ritonavir: maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Patients with renal or hepatic impairment should not be given colchicine with PREZISTA/ritonavir.
Antimycobacterial: rifabutin	↑ darunavir ↑ rifabutin ↑ 25-O-desacetylrifabutin	Dose reduction of rifabutin by at least 75% of the usual dose (300 mg once daily) is recommended (i.e., a maximum dose of 150 mg every other day). Increased monitoring for adverse events is warranted in patients receiving this combination and further dose reduction of rifabutin may be necessary.
The reference regimen for rifabutin was 300 mg once daily	↑ darunavir ↑ rifabutin ↑ 25-O-desacetylrifabutin
β-Blockers: metoprolol, timolol	↑ beta-blockers	Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir.
Benzodiazepines: parenterally administered midazolam	↑ midazolam	Concomitant use of parenteral midazolam with PREZISTA/ritonavir may increase plasma concentrations of midazolam. Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Co-administration of oral midazolam with PREZISTA/ritonavir is CONTRAINDICATED.
Calcium Channel Blockers: felodipine, nifedipine, nicardipine	↑ calcium channel blockers	Plasma concentrations of calcium channel blockers (e.g., felodipine, nifedipine, nicardipine) may increase when PREZISTA/ritonavir are co-administered. Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid: Systemic: dexamethasone	↓ darunavir	Systemic dexamethasone induces CYP3A and can thereby decrease darunavir plasma concentrations. This may result in loss of therapeutic effect to PREZISTA.
Corticosteroid: Inhaled/Nasal: fluticasone	↑ fluticasone	Concomitant use of inhaled fluticasone and PREZISTA/ritonavir may increase plasma concentrations of fluticasone. Alternatives should be considered, particularly for long-term use.
Endothelin receptor antagonists: bosentan	↑ bosentan	Co-administration of bosentan in patients on PREZISTA/ritonavir: In patients who have been receiving PREZISTA/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Co-administration of PREZISTA/ritonavir in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of PREZISTA/ritonavir. After at least 10 days following the initiation of PREZISTA/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Hepatitis C Virus (HCV) Direct-Acting Agents: NS3-4A protease inhibitors: boceprevir telaprevir	↓ darunavir ↓ boceprevir ↓ telaprevir	Concomitant administration of PREZISTA/ritonavir and boceprevir or telaprevir resulted in reduced steady-state exposures to darunavir and boceprevir or telaprevir. It is not recommended to co-administer boceprevir or telaprevir and PREZISTA/ritonavir.
HMG-CoA Reductase Inhibitors: pravastatin, atorvastatin, rosuvastatin	↑ pravastatin ↑ atorvastatin ↑ rosuvastatin	Titrate atorvastatin, pravastatin or rosuvastatin dose carefully and use the lowest necessary dose while monitoring for safety. Do not exceed atorvastatin 20 mg/day.
Immunosuppressants: cyclosporine, tacrolimus, sirolimus	↑ immunosuppressants	Plasma concentrations of cyclosporine, tacrolimus or sirolimus may be increased when co-administered with PREZISTA/ritonavir. Therapeutic concentration monitoring of the immunosuppressive agent is recommended when co-administered with PREZISTA/ritonavir.
Inhaled beta agonist: salmeterol	↑ salmeterol	Concurrent administration of salmeterol and PREZISTA/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic/Treatment of Opioid Dependence: methadone, buprenorphine, buprenorphine/naloxone	↓ methadone ↔ buprenorphine, naloxone ↑ norbuprenorphine (metabolite)	No adjustment of methadone dosage is required when initiating co-administration of PREZISTA/ritonavir. However, clinical monitoring is recommended as the dose of methadone during maintenance therapy may need to be adjusted in some patients. No dose adjustment for buprenorphine or buprenorphine/naloxone is required with concurrent administration of PREZISTA/ritonavir. Clinical monitoring is recommended if PREZISTA/ritonavir and buprenorphine or buprenorphine/naloxone are coadministered.
Neuroleptics: risperidone, thioridazine	↑ neuroleptics	A dose decrease may be needed for these drugs when co-administered with PREZISTA/ritonavir.
Oral Contraceptives/estrogen: ethinyl estradiol, norethindrone	↓ ethinyl estradiol ↓ norethindrone	Plasma concentrations of ethinyl estradiol are decreased due to induction of its metabolism by ritonavir. Alternative methods of nonhormonal contraception are recommended.
PDE-5 inhibitors: sildenafil, vardenafil, tadalafil	↑ PDE-5 inhibitors (only the use of sildenafil at doses used for treatment of erectile dysfunction has been studied with PREZISTA/ritonavir)	Co-administration with PREZISTA/ritonavir may result in an increase in PDE-5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances and priapism. Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Use of sildenafil is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications (4) ]. The following dose adjustments are recommended for use of tadalafil with PREZISTA/ritonavir: Co-administration of tadalafil in patients on PREZISTA/ritonavir: In patients receiving PREZISTA/ritonavir for at least one week, start tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Co-administration of PREZISTA/ritonavir in patients on tadalafil: Avoid use of tadalafil during the initiation of PREZISTA/ritonavir. Stop tadalafil at least 24 hours prior to starting PREZISTA/ritonavir. After at least one week following the initiation of PREZISTA/ritonavir, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE-5 inhibitors for erectile dysfunction: Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg dose in 72 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours can be used with increased monitoring for PDE-5 inhibitor-associated adverse events.
Selective Serotonin Reuptake Inhibitors (SSRIs): sertraline, paroxetine	↔ darunavir ↓ sertraline ↓ paroxetine	If sertraline or paroxetine is co-administered with PREZISTA/ritonavir, the recommended approach is a careful dose titration of the SSRI based on a clinical assessment of antidepressant response. In addition, patients on a stable dose of sertraline or paroxetine who start treatment with PREZISTA/ritonavir should be monitored for antidepressant response.

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Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of aripiprazole tablets with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole tablets alone [seeCLINICALPHARMACOLOGY( 12.3)].	Withconcomitant use of aripiprazole tablets with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole tablets dosage [see DOSAGEANDADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of aripiprazole tablets and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole tablets alone [see CLINICALPHARMACOLOGY (12.3)].	Withconcomitant use of aripiprazole tablets with a strong CYP3A4 inducer, consider increasing the aripiprazole tablets dosage [see DOSAGE ANDADMINISTRATION( 2.7)].
AntihypertensiveDrugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor bloodpressure and adjust dose accordingly [seeWARNINGS AND PRECAUTIONS (5.8)].
Benzodiazepines(e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [seeWARNINGSANDPRECAUTIONS (5.8)]	Monitor sedation and blood pressure. Adjust dose accordingly.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T ₄ and T ₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT ₄. Continued administration results in a decrease in serum T ₄ and normal FT ₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T ₄ and T ₃ to TBG and transthyretin. An initial increase in serum FT ₄, is followed by return of FT ₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T ₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T ₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T ₄ to T ₃, leading to decreased T ₃ levels. However, serum T ₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T ₃ and T ₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T ₃ concentrations by 30% with minimal change in serum T ₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T ₃ and T ₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 18: Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Co-administered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9-Hydroxy- Risperidone(RatioChange relative to reference)		Risperidone Dose Recommendation
Co-administered Drug	Co-administered Drug	Risperidone	AUC	C_max	Risperidone Dose Recommendation
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Oral hypoglycemics
Coumarin-type anticoagulants
Phenytoin
Cyclosporine
Rifampin
Theophylline
Voriconazole
Tofacitinib
Oral Contraceptives
Hydrochlorothiazide
Amitriptyline, nortriptyline
Azithromycin
Calcium Channel Blockers
Cyclophosphamide

Quinidine
Halofantrine
Losartan
Non-steroidal anti-inflammatory drugs
Saquinavir
Vinca Alkaloids
Zidovudine
Terfenadine
Cisapride
Astemizole
Rifabutin
Tacrolimus
Short-acting benzodiazepines

Triazolam
Pimozide
Alfentanil
Amphotericin B
Carbamazepine
Celecoxib
Fentanyl
HMG-CoA reductase inhibitors
Methadone
Prednisone
Sirolimus
Vitamin A

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AED Coadministered	AED Concentration	Topiramate Concentration
^a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. ^b = Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. NE = Not Evaluated
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C_max and AUCτ)	Recommendations for Drug Dosage Adjustment/Comments
Sirolimus* (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin* (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (400 mg q 24h) (CYP3A4 Inhibition) Efavirenz (300 mg q 24h) (CYP3A4 Inhibition)	Significantly Increased Slight decrease in AUC_t	Contraindicated When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)(CYP3A4 Inhibition) Low-dose Ritonavir (100 mg q12h)	No Significant Effect of Voriconazole on Ritonavir C_max or AUCτ Slight Decrease in Ritonavir C_max and AUCτ	Contraindicated because of significant reduction of voriconazole C_max and AUCτ
		Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole C_max and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated
Cyclosporine* (CYP3A4 Inhibition)	AUCτ Significantly Increased; No Significant Effect on C_max	When initiating therapy with voriconazole in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
Methadone*** (CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see DRUG INTERACTIONS (7)]
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see DRUG INTERACTIONS (7)].
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see DRUG INTERACTIONS (7)].
NSAIDs**** including ibuprofen and diclofenac (CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed. [see DRUG INTERACTIONS (7)].
Tacrolimus* (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with voriconazole in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin* (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)**	Increased	Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin* (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	Monitor PT or other suitable anticoagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole* (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with voriconazole in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects on Indinavir Exposure	No dosage adjustment for indinavir when coadministered with voriconazole tablets
	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIs***** (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.
Everolimus (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Concomitant administration of voriconazole and everolimus is not recommended

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Inhibitors of CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6
Clinical Impact:	Methadone undergoes hepatic N-demethylation by several cytochrome P450 (CYP) isoforms, including CYP3A4, CYP2B6, CYP2C19, CYP2C9, and CYP2D6. The concomitant use of methadone hydrochloride tablets and CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitors can increase the plasma concentration of methadone, resulting in increased or prolonged opioid effects, and may result in a fatal overdose, particularly when an inhibitor is added after a stable dose of methadone hydrochloride tablets is achieved. These effects may be more pronounced with concomitant use of drugs that inhibit more than one of the CYP enzymes listed above. After stopping a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitor, as the effects of the inhibitor decline, the methadone plasma concentration can decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or withdrawal symptoms in patients physically dependent on methadone.
Intervention:	If concomitant use is necessary, consider dosage reduction of methadone hydrochloride tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4, CYP2B6, CYP2C19, CYP2C9, or CYP2D6 inhibitor is discontinued, follow patients for signs of opioid withdrawal and consider increasing the methadone hydrochloride tablets dosage until stable drug effects are achieved.
Examples:	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir), fluconazole, fluvoxamine, some selective serotonin reuptake inhibitors (SSRIs) (e.g., sertraline, fluvoxamine)
Inducers of CYP3A4, CYP2B6, CYP2C19, or CYP2C9
Clinical Impact:	The concomitant use of methadone hydrochloride tablets and CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducers can decrease the plasma concentration of methadone [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of withdrawal symptoms in patients physically dependent on methadone. These effects could be more pronounced with concomitant use of drugs that can induce multiple CYP enzymes. After stopping a CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducer, as the effects of the inducer decline, the methadone plasma concentration can increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression, sedation, or death.
Intervention:	If concomitant use is necessary, consider increasing the methadone hydrochloride tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4, CYP2B6, CYP2C19, or CYP2C9 inducer is discontinued, consider methadone hydrochloride tablets dosage reduction and monitor for signs of respiratory depression and sedation.
Examples:	Rifampin, carbamazepine, phenytoin, St. John’s Wort, Phenobarbital
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.6)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Potentially Arrhythmogenic Agents
Clinical Impact:	Pharmacodynamic interactions may occur with concomitant use of methadone and potentially arrhythmogenic agents or drugs capable of inducing electrolyte disturbances (hypomagnesemia, hypokalemia).
Intervention:	Monitor patients closely for cardiac conduction changes.
Examples:	Drugs known to have potential to prolong QT interval: Class I and III antiarrhythmics, some neuroleptics and tricyclic antidepressants, and calcium channel blockers. Drugs capable of inducing electrolyte disturbances: Diuretics, laxatives, and, in rare cases, mineralocortocoid hormones.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions (5.8)].
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue methadone hydrochloride tablets if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.8)] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
Intervention:	The use of methadone hydrochloride tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of methadone hydrochloride tablets and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Methadone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of methadone hydrochloride tablets and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when methadone hydrochloride tablets are used concomitantly with anticholinergic drugs.

Table name:

Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistatcontaining products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
* The interaction between immediate-release nevirapine tablets and the drug was evaluated in a clinical study. The results of drug interaction studies with immediate-release nevirapine tablets are expected to also apply to nevirapine extended-release tablets.
Drug Name	Effect on Concentration of Nevirapine or Concomitant Drug	Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir*	↓ Atazanavir ↑ Nevirapine	Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir* Fosamprenavir/Ritonavir*	↓ Amprenavir ↑ Nevirapine ↓ Amprenavir ↑ Nevirapine	Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir*	↓ Indinavir	The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir*	↓Lopinavir	Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra^® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir*	↓ Nelfinavir M8 Metabolite ↓ Nelfinavir C_min	The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/ritonavir	The interaction between nevirapine and saquinavir/ritonavir has not been evaluated	The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz*	↓ Efavirenz	The appropriate doses of these combinations with respect to safety and efficacy have not been established.
Delavirdine Etravirine Rilpivirine		Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.
Hepatitis C Antiviral Agents
Boceprevir	Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine.	Nevirapine and boceprevir should not be coadministered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy.
Telaprevir	Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir.	Nevirapine and telaprevir should not be coadministered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events.
Other Agents
Analgesics: Methadone*	↓ Methadone	Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics: Amiodarone, disopyramide, lidocaine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Antibiotics: Clarithromycin*	↓ Clarithromycin ↑ 14-OH clarithromycin	Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Rifabutin*	↑ Rifabutin	Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin*	↓ Nevirapine	Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants: Carbamazepine, clonazepam, ethosuximide	Plasma concentrations of nevirapine and the anticonvulsant may be decreased.	Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals: Fluconazole*	↑ Nevirapine	Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Ketoconazole*	↓ Ketoconazole	Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Itraconazole	↓ Itraconazole	Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics: Warfarin	Plasma concentrations may be increased.	Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers: Diltiazem, nifedipine, verapamil	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Cancer chemotherapy: Cyclophosphamide	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Ergot alkaloids: Ergotamine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Motility agents: Cisapride	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Opiate agonists: Fentanyl	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Oral contraceptives: Ethinyl estradiol and Norethindrone*	↓ Ethinyl estradiol ↓ Norethindrone	Despite lower ethinyl estradiol and norethindrone exposures when coadministered with nevirapine, literature reports suggest that nevirapine has no effect on pregnancy rates among HIV-infected women on combined oral contraceptives. When coadministered with nevirapine extended-release tablets, no dose adjustment of ethinyl estradiol or norethindrone is needed when used in combination for contraception When oral contraceptives are used for hormonal regulation during nevirapine extended-release tablets therapy, the therapeutic effect of the hormonal therapy should be monitored.

Table name:

Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( 7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( 7)
Phenytoin	Monitor phenytoin level ( 7)
Methotrexate	Monitor for methotrexate toxicity ( 7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine ( 7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin ( 7)

Table name:

Interacting Agent	Examples
Drugs whose efficacy is impaired by phenytoin
Azoles	Fluconazole, ketoconazole, itraconazole, posaconazole, voriconazole
Antineoplastic agents	Irinotecan, paclitaxel, teniposide
Delavirdine	Phenytoin can substantially reduce the concentrations of delavirdine. This can lead to loss of virologic response and possible resistance [see Contraindications (4)].
Neuromuscular blocking agents	Cisatracurium, pancuronium, rocuronium and vecuronium: resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents has occurred in patients chronically administered phenytoin. Whether or not phenytoin has the same effect on other non-depolarizing agents is unknown. Prevention or Management: Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher.
Warfarin	Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin
Other	Corticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D
Drugs whose level is decreased by phenytoin
Antiepileptic drugs^a	Carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine
Antilipidemic agents	Atorvastatin, fluvastatin, simvastatin
Antiviral agents	Efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir Fosamprenavir: phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir
Calcium channel blockers	Nifedipine, nimodipine, nisoldipine, verapamil
Other	Albendazole (decreases active metabolite), chlorpropamide, clozapine, cyclosporine, digoxin, folic acid, methadone, mexiletine, praziquantel, quetiapine

Table name:

Table 3. Clinically Significant Drug Interactions with naproxen or sumatriptan
Ergot-Containing Drugs
Clinical Impact:	Ergot-containing drugs have been reported to cause prolonged vasospastic reactions.
Intervention:	Because these effects may be additive, coadministration of TREXIMET and ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) within 24 hours of each other is contraindicated.
Monoamine Oxidase-A Inhibitors
Clinical Impact:	MAO-A inhibitors increase systemic exposure of orally administered sumatriptan by 7-fold.
Intervention:	The use of TREXIMET in patients receiving MAO-A inhibitors is contraindicated.
Other 5-HT₁ Agonists
Clinical Impact:	5-HT₁ agonist drugs can cause vasospastic effects.
Intervention:	Because these effects may be additive, coadministration of TREXIMET and other 5 HT₁ agonists (e.g., triptans) within 24 hours of each other is contraindicated.
Drugs That Interfere with Hemostasis
Clinical Impact:	Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of TREXIMET with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.16)].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].
Intervention:	Concomitant use of TREXIMET and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.16)].
Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome
Clinical Impact:	Cases of serotonin syndrome have been reported during coadministration of triptans and SSRIs, SNRIs, TCAs, and MAO inhibitors [see Warnings and Precautions (5.11)].
Intervention:	Discontinue TREXIMET if serotonin syndrome is suspected.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of TREXIMET and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained [see Warnings and Precautions (5.8)]. During concomitant use of TREXIMET and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.8)].
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of TREXIMET with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.8, 5.12)].
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of TREXIMET and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of TREXIMET and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant administration of some NSAIDs with high-dose methotrexate therapy has been reported to elevate and prolong serum methotrexate levels, resulting in deaths from severe hematologic and gastrointestinal toxicity. Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of TREXIMET and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of NSAIDs and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention:	During concomitant use of TREXIMET and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of NSAIDs and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of TREXIMET and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly. The clinical significance of this is unknown.
Intervention:	Reduce the frequency of administration of Treximet when given concurrently with probenecid.

Table name:

DRUG	DISCRIPTION OF INTERACTION
Sulfonylureas	Hypoglycemia potentiated
Methotrexate	Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants	Increased bleeding

Table name:

Specific Drugs Reported
also: other medications affecting blood elements which may modify hemostasis dietary deficiencies prolonged hot weather unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported.
acetaminophen alcohol† allopurinol aminosalicylic acid amiodarone HCl argatroban aspirin atenolol atorvastatin† azithromycin bivalirudin capecitabine cefamandole cefazolin cefoperazone cefotetan cefoxitin ceftriaxone celecoxib cerivastatin chenodiol chloramphenicol chloral hydrate† chlorpropamide cholestyramine† cimetidine ciprofloxacin cisapride clarithromycin clofibrate cyclophosphamide† danazol dextran dextrothyroxine diazoxide	diclofenac dicumarol diflunisal disulfiram doxycycline erythromycin esomeprazole ethacrynic acid ezetimibe fenofibrate fenoprofen fluconazole fluorouracil fluoxetine flutamide fluvastatin fluvoxamine gefitinib gemifibrozil glucagon halothane heparin ibuprofen ifosfamide indomethacin influenza virus vaccine itraconazole ketoprofen ketorolac lansoprazole lepirudin levamisole levofloxacin levothyroxine liothyronine	lovastatin mefenamic acid methimazole† methyldopa methylphenidate methylsalicylate ointment (topical) metronidazole miconazole (intravaginal, oral, systemic) moricizine hydrochloride† nalidixic acid naproxen neomycin norfloxacin ofloxacin olsalazine omeprazole oxandrolone oxaprozin oxymetholone pantoprazole paroxetine penicillin G, intravenous pentoxifylline phenylbutazone phenytoin† piperacillin piroxicam pravastatin† prednisone† propafenone	propoxyphene propranolol propylthiouracil† quinidine quinine rabeprazole ranitidine† rofecoxib sertraline simvastatin stanozolol streptokinase sulfamethizole sulfamethoxazole sulfinpyrazone sulfisoxazole sulindac tamoxifen tetracycline thyroid ticarcillin ticlopidine tissue plasminogen activator (t-PA) tolbutamide tramadol trimethoprim/ sulfamethoxazole urokinase valdecoxib valproate vitamin E warfarin overdose zafirlukast zileuton

Table name:

Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine, danazol	Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 7: Selected Drug Interactions in Adults
Concomitant Drug Class: Drug Name	Effect on Concentration of Raltegravir	Clinical Comment
HIV-1-Antiviral Agents
atazanavir	↑	Atazanavir, a strong inhibitor of UGT1A1, increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
atazanavir/ritonavir	↑	Atazanavir/ritonavir increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
efavirenz	↓	Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
etravirine	↓	Etravirine reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
tipranavir/ritonavir	↓	Tipranavir/ritonavir reduces plasma concentrations of raltegravir. However, since comparable efficacy was observed for this combination relative to other ISENTRESS-containing regimens in Phase 3 studies 018 and 019, no dose adjustment is recommended.
Other Agents
omeprazole	↑	Coadministration of medicinal products that increase gastric pH (e.g., omeprazole) may increase raltegravir levels based on increased raltegravir solubility at higher pH. However, since concomitant use of ISENTRESS with proton pump inhibitors and H2 blockers did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
rifampin	↓	Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of raltegravir. The recommended dosage of ISENTRESS is 800 mg twice daily during coadministration with rifampin.

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Table 2. Clinically Significant Drug Interactions with Diclofenac
Drugs That Interfere with Hemostasis
Clinical Impact:	Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of diclofenac sodium delayed-release tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS: Hematologic Toxicity ).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ).
Intervention:	Concomitant use of diclofenac sodium delayed-release tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS: Hematologic Toxicity ). Diclofenac sodium delayed-release tablets are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of diclofenac sodium delayed-release tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS: Renal Toxicity and Hyperkalemia ). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS: Renal Toxicity and Hyperkalemia ).
Digoxin
Clinical Impact:	The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance . The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of diclofenac sodium delayed-release tablets and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ) .
Intervention:	The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of diclofenac sodium delayed-release tablets and pemetrexed may increase the risk of pemetrexed‑ associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or Inducers:
Clinical Impact:	Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Co-administration of diclofenac with CYP2C9 inhibitors (e.g. voriconazole) may enhance the exposure and toxicity of diclofenac whereas co‑administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of diclofenac.
Intervention:	A dosage adjustment may be warranted when diclofenac is administered with CYP2C9 inhibitors or inducers (see CLINICAL PHARMACOLOGY: Pharmacokinetics ).

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Figure 2: Effect of venlafaxine on the pharmacokinetics interacting drugs and their active metabolites.

Table name: Tolterodine (patients deficient in CYP2D6 activity) Theophylline Use With Caution Midazolam Use With Caution Use With Caution

Table 8: Clinically Significant Drug Interactions with Clarithromycin
Drugs That Are Affected By Clarithromycin
Drug(s) with Pharmacokinetics Affected by Clarithromycin	Recommendation	Comments
Antiarrhythmics:
Disopyramide Quinidine Dofetilide Amiodarone Sotalol Procainamide	Not Recommended	Disopyramide, Quinidine: There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs [see Warnings and Precautions (5.3)]. Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine. There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.
Digoxin	Use With Caution	Digoxin: Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are co-administered, inhibition of Pgp by clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range.
Oral Anticoagulants:
Warfarin	Use With Caution	Oral anticoagulants: Spontaneous reports in the postmarketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously [see Warnings and Precautions (5.4)].
Antiepileptics:
Carbamazepine	Use With Caution	Carbamazepine: Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered. Increased serum concentrations of carbamazepine were observed in clinical trials with clarithromycin. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with carbamazepine.
Antifungals:
Itraconazole	Use With Caution	Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly (see also Itraconazole under “Drugs That Affect Clarithromycin” in the table below). Clarithromycin may increase the plasma concentrations of itraconazole. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions.
Fluconazole	No Dose Adjustment	Fluconazole: [see Pharmacokinetics (12.3)]
Anti-Gout Agents:
Colchicine (in patients with renal or hepatic impairment) Colchicine (in patients with normal renal and hepatic function)	Contraindicated Use With Caution	Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. The dose of colchicine should be reduced when co-administered with clarithromycin in patients with normal renal and hepatic function [see Contraindications (4.4)and Warnings and Precautions (5.4)].
Antipsychotics:
Pimozide	Contraindicated	Pimozide: [See Contraindications (4.2)]
Quetiapine		Quetiapine: Quetiapine is a substrate for CYP3A4, which is inhibited by clarithromycin. Co-administration with clarithromycin could result in increased quetiapine exposure and possible quetiapine related toxicities. There have been postmarketing reports of somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation during concomitant administration. Refer to quetiapine prescribing information for recommendations on dose reduction if co-administered with CYP3A4 inhibitors such as clarithromycin.
Antispasmodics:

Use With Caution	Tolterodine: The primary route of metabolism for tolterodine is via CYP2D6. However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when co-administered with clarithromycin.
Antivirals:
Atazanavir	Use With Caution	Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)].
Saquinavir (in patients with decreased renal function)		Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction (see Saquinavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)].
Ritonavir Etravirine		Ritonavir, Etravirine: (see Ritonavir and Etravirine under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)].
Maraviroc		Maraviroc: Clarithromycin may result in increases in maraviroc exposures by inhibition of CYP3A metabolism. See Selzentry^® prescribing information for dose recommendation when given with strong CYP3A inhibitors such as clarithromycin.
Boceprevir (in patients with normal renal function) Didanosine	No Dose Adjustment	Boceprevir: Both clarithromycin and boceprevir are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when co-administered. No dose adjustments are necessary for patients with normal renal function (see Victrelis^® prescribing information).
Zidovudine		Zidovudine: Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Administration of clarithromycin and zidovudine should be separated by at least two hours [see Pharmacokinetics (12.3)]. The impact of co-administration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated.
Calcium Channel Blockers:
Verapamil	Use With Caution	Verapamil: Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, [see Warnings and Precautions (5.4)].
Amlodipine Diltiazem		Amlodipine, Diltiazem: [See Warnings and Precautions (5.4)]
Nifedipine		Nifedipine: Nifedipine is a substrate for CYP3A. Clarithromycin and other macrolides are known to inhibit CYP3A. There is potential of CYP3A-mediated interaction between nifedipine and clarithromycin. Hypotension and peripheral edema were observed when clarithromycin was taken concomitantly with nifedipine [see Warnings and Precautions (5.4)].
Ergot Alkaloids:
Ergotamine Dihydroergotamine	Contraindicated	Ergotamine, Dihydroergotamine: Postmarketing reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4.6)].
Gastroprokinetic Agents:
Cisapride	Contraindicated	Cisapride: [See Contraindications (4.2)]
HMG-CoA Reductase Inhibitors:
Lovastatin Simvastatin	Contraindicated	Lovastatin, Simvastatin, Atorvastatin, Pravastatin, Fluvastatin: [See Contraindications (4.5)and Warnings and Precautions (5.4)]
Atorvastatin Pravastatin	Use With Caution
Fluvastatin	No Dose Adjustment
Hypoglycemic Agents:
Nateglinide Pioglitazone Repaglinide Rosiglitazone	Use With Caution	Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone: [See Warnings and Precautions (5.4)and Adverse Reactions (6.2)]
Insulin		Insulin: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]
Immunosuppressants:
Cyclosporine	Use With Caution	Cyclosporine: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine.
Tacrolimus		Tacrolimus: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with tacrolimus.
Phosphodiesterase inhibitors:
Sildenafil Tadalafil Vardenafil	Use With Caution	Sildenafil, Tadalafil, Vardenafil: Each of these phosphodiesterase inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant administration of clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil, or vardenafil will result in increased exposure of these phosphodiesterase inhibitors. Co-administration of these phosphodiesterase inhibitors with clarithromycin is not recommended. Increased systemic exposure of these drugs may occur with clarithromycin; reduction of dosage for phosphodiesterase inhibitors should be considered (see their respective prescribing information).
Proton Pump Inhibitors:
Omeprazole	No Dose Adjustment	Omeprazole: The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when coadministered with clarithromycin as a result of increased omeprazole exposures [see Pharmacokinetics (12.3)] (see also Omeprazole under “Drugs That Affect Clarithromycin” in the table below).
Xanthine Derivatives:


Theophylline: Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations [see Pharmacokinetics (12.3)]. Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range.
Triazolobenzodiazepines and Other Related Benzodiazepines:

Use With Caution	Midazolam: When oral midazolam is co-administered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated [see Warnings and Precautions (5.4)and Pharmacokinetics (12.3)].
Alprazolam Triazolam		Triazolam, Alprazolam: Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is co-administered with clarithromycin. There have been postmarketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested. In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines.
Temazepam Nitrazepam Lorazepam	No Dose Adjustment	Temazepam, Nitrazepam, Lorazepam: For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.
Cytochrome P450 Inducers:
Rifabutin	Use With Caution	Rifabutin: Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis (see Rifabutin under “Drugs That Affect Clarithromycin” in the table below).
Other Drugs Metabolized by CYP3A:
Alfentanil Bromocriptine Cilostazol Methylprednisole Vinblastine Phenobarbital St. John’s Wort	Use With Caution	There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort.
Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A:
Hexobarbital Phenytoin Valproate	Use With Caution	There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.
Drugs that Affect Clarithromycin
Drug(s) that Affect the Pharmacokinetics of Clarithromycin	Recommendation	Comments
Antifungals:
Itraconazole
Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions (see also Itraconazole under “Drugs That Are Affected By Clarithromycin” in the table above).
Antivirals:
Atazanavir	Use With Caution	Atazanavir: When clarithromycin is co-administered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology (12.3)]. Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.
Ritonavir (in patients with decreased renal function)		Ritonavir: Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with ritonavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium[see Pharmacokinetics (12.3)]. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.
Saquinavir (in patients with decreased renal function)		Saquinavir: When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (refer to ritonavir above) [see Pharmacokinetics (12.3)].
Etravirine		Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.
Saquinavir (in patients with normal renal function)	No Dose Adjustment
Ritonavir (in patients with normal renal function)
Proton Pump Inhibitors:
Omeprazole
Omeprazole: Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole [see Pharmacokinetics (12.3)].
Miscellaneous Cytochrome P450 Inducers:
Efavirenz Nevirapine Rifampicin Rifabutin Rifapentine	Use With Caution	Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are Affected By Clarithromycin” in the table above).

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C Protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase ^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide ^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
*Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	Cmax
Enzyme (CYP2D6) inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not Needed

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cation or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products.
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agent	Carefully monitor blood glucose (5.11, 7.3)

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Table 5: Significant Drug Interactions with BUTRANS
Benzodiazepines
Clinical Impact:	There have been a number of reports regarding coma and death associated with the misuse and abuse of the combination of buprenorphine and benzodiazepines. In many, but not all of these cases, buprenorphine was misused by self-injection of crushed buprenorphine tablets. Preclinical studies have shown that the combination of benzodiazepines and buprenorphine altered the usual ceiling effect on buprenorphine-induced respiratory depression, making the respiratory effects of buprenorphine appear similar to those of full opioid agonists.
Intervention:	Closely monitor patients with concurrent use of BUTRANS and benzodiazepines. Warn patients that it is extremely dangerous to self-administer benzodiazepines while taking BUTRANS, and warn patients to use benzodiazepines concurrently with BUTRANS only as directed by their physician.
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effects, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Inhibitors of CYP3A4
Clinical Impact:	The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of BUTRANS is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease [see Clinical Pharmacology (12.3)], potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to buprenorphine.
Intervention:	If concomitant use is necessary, consider dosage reduction of BUTRANS until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the BUTRANS dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples:	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact:	The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine [see Clinical Pharmacology (12.3)], potentially resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both therapeutic effects and adverse reactions and may cause serious respiratory depression.
Intervention:	If concomitant use is necessary, consider increasing the BUTRANS dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider BUTRANS dosage reduction and monitor for signs of respiratory depression.
Examples:	Rifampin, carbamazepine, phenytoin
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue BUTRANS if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)]
Intervention:	The use of BUTRANS is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of BUTRANS and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine
Muscle Relaxants
Clinical Impact:	Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients receiving muscle relaxants and BUTRANS for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of BUTRANS and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of opioid analgesics, including buprenorphine, and anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when BUTRANS is used concomitantly with anticholinergic drugs.

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Figure 5: Mean Standing Systolic Blood Pressure Change from Baseline

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Drugs That Interfere with Hemostasis
Clinical Impact:	• Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	• During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 3 Established and Other Potentially SignificantThis table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
Concomitant Drug Class: Drug Name	Effect	Clinical Comment
HIV antiviral agents
Protease inhibitor: atazanavir	↓atazanavir ↑ tenofovir	Coadministration of atazanavir with ATRIPLA is not recommended. Coadministration of atazanavir with either efavirenz or tenofovir DF decreases plasma concentrations of atazanavir. The combined effect of efavirenz plus tenofovir DF on atazanavir plasma concentrations is not known. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA.
Protease inhibitor: fosamprenavir calcium	↓ amprenavir	Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and ATRIPLA with respect to safety and efficacy have not been established.
		Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when ATRIPLA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when ATRIPLA is administered with fosamprenavir plus ritonavir twice daily.
Protease inhibitor: indinavir	↓ indinavir	The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz.
Protease inhibitor: lopinavir/ritonavir	↓ lopinavir ↑ tenofovir	Do not use once daily administration of lopinavir/ritonavir. Dose increase of lopinavir/ritonavir is recommended for all patients when coadministered with efavirenz. Refer to the full prescribing information for lopinavir/ritonavir for guidance on coadministration with efavirenz- or tenofovir-containing regimens, such as ATRIPLA. Patients should be monitored for tenofovir-associated adverse reactions.
Protease inhibitor: ritonavir	↑ ritonavir ↑ efavirenz	When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when ATRIPLA is used in combination with ritonavir.
Protease inhibitor: saquinavir	↓ saquinavir	Appropriate doses of the combination of efavirenz and saquinavir/ritonavir with respect to safety and efficacy have not been established.
CCR5 co-receptor antagonist: maraviroc	↓ maraviroc	Efavirenz decreases plasma concentrations of maraviroc. Refer to the full prescribing information for maraviroc for guidance on coadministration with ATRIPLA.
NRTI: didanosine	↑ didanosine	Coadministration of ATRIPLA and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions including pancreatitis, lactic acidosis, and neuropathy. A dose reduction of didanosine is recommended when coadministered with tenofovir DF. For additional information on coadministration with tenofovir DF-containing products, please refer to the didanosine prescribing information.
NNRTI: Other NNRTIs	↑ or ↓ efavirenz and/or NNRTI	Combining two NNRTIs has not been shown to be beneficial. ATRIPLA contains efavirenz and should not be coadministered with other NNRTIs.
Integrase strand transfer inhibitor: raltegravir	↓ raltegravir	Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
Hepatitis C antiviral agents
Protease inhibitor: boceprevir	↓ boceprevir	Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with efavirenz, which may result in loss of therapeutic effect. The combination should be avoided.
Protease inhibitor: simeprevir	↓ simeprevir ↔ efavirenz	Concomitant administration of simeprevir with efavirenz is not recommended because it may result in loss of therapeutic effect of simeprevir.
NS5A inhibitor/NS5B polymerase inhibitor : ledipasvir/sofosbuvir	↑ tenofovir	Patients receiving ATRIPLA and HARVONI™ (ledipasvir/sofosbuvir) concomitantly should be monitored for adverse reactions associated with tenofovir DF.
Other agents
Anticoagulant: warfarin	↑ or ↓ warfarin	Plasma concentrations and effects potentially increased or decreased by efavirenz.
Anticonvulsants: carbamazepine	↓ carbamazepine ↓ efavirenz	There are insufficient data to make a dose recommendation for ATRIPLA. Alternative anticonvulsant treatment should be used.
phenytoin phenobarbital	↓ anticonvulsant ↓ efavirenz	Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
Antidepressants: bupropion	↓ buproprion	The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded.
sertraline	↓ sertraline	Increases in sertraline dose should be guided by clinical response.
Antifungals: itraconazole	↓ itraconazole ↓ hydroxy-itraconazole	Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
ketoconazole	↓ ketoconazole	Drug interaction trials with ATRIPLA and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole.
posaconazole	↓ posaconazole	Avoid concomitant use unless the benefit outweighs the risks.
Anti-infective: clarithromycin	↓ clarithromycin ↑ 14-OH metabolite	Clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of ATRIPLA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with ATRIPLA.
Antimycobacterial: rifabutin	↓ rifabutin	Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
rifampin	↓ efavirenz	If ATRIPLA is coadministered with rifampin to patients weighing 50 kg or more, an additional 200 mg/day of efavirenz is recommended.
Antimalarials: artemether/lumefantrine	↓ artemether ↓ dihydroartemisinin ↓ lumefantrine	Artemether/lumefantrine should be used cautiously with ATRIPLA because decreased artemether, dihydroartemisinin (active metabolite of artemether), and/or lumefantrine concentrations may result in a decrease of antimalarial efficacy of artemether/lumefantrine.
Calcium channel blockers: diltiazem	↓ diltiazem ↓ desacetyl diltiazem ↓ N-monodes-methyl diltiazem	Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of ATRIPLA is necessary when administered with diltiazem.
Others (e.g., felodipine, nicardipine, nifedipine, verapamil)	↓ calcium channel blocker	No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker).
HMG-CoA reductase inhibitors: atorvastatin pravastatin simvastatin	↓ atorvastatin ↓ pravastatin ↓ simvastatin	Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with efavirenz. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
Hormonal contraceptives:
Oral: ethinyl estradiol/norgestimate	↓ active metabolites of norgestimate	A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed.
Implant: etonogestrel	↓ etonogestrel	A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.
Immunosuppressants: cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A	↓ immuno-suppressant	Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by efavirenz. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with ATRIPLA.
Narcotic analgesic: methadone	↓ methadone	Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.

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Muscle Relaxants
Clinical Impact:	Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Morphine Sulfate Injection and/or the muscle relaxant as necessary.
Cimetidine
Clinical Impact:	The concomitant administration of morphine sulfate and cimetidine has been reported to precipitate apnea, confusion and muscle twitching in an isolated report.
Intervention:	Monitor patients for increased respiratory and CNS depression when receiving cimetidine concomitantly with Morphine Sulfate Injection.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when Morphine Sulfate Injection is used concomitantly with anticholinergic drugs.

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Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir), Hepatitis C Protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Interacting Agent	Examples
Drugs that may increase phenytoin serum levels
Antiepileptic drugs	Ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate
Azoles	Fluconazole, ketoconazole, itraconazole, miconazole, voriconazole
Antineoplastic agents	Capecitabine, fluorouracil
Antidepressants	Fluoxetine, fluvoxamine, sertraline
Gastric acid reducing agents	H₂ antagonists (cimetidine), omeprazole
Sulfonamides	Sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole trimethoprim
Other	Acute alcohol intake, amiodarone, chloramphenicol, chlordiazepoxide, disulfiram, estrogen, fluvastatin, isoniazid, methylphenidate, phenothiazines, salicylates, ticlopidine, tolbutamide, trazodone, warfarin
Drugs that may decrease phenytoin serum levels
Antineoplastic agents usually in combination	Bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate
Antiviral agents	Fosamprenavir, nelfinavir, ritonavir
Antiepileptic drugs	Carbamazepine, vigabatrin
Other	Chronic alcohol abuse, diazepam, diazoxide, folic acid, reserpine, rifampin, St. John’s wort^b, theophylline
Drugs that may either increase or decrease phenytoin serum levels
Antiepileptic drugs	Phenobarbital, valproate sodium, valproic acid

Table name:

Drugs That Interfere with Hemostasis
Clinical Impact:	• Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	• During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

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Table 13. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓lamotrigine ↓levonorgestrel	Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels
Lopinavir/ ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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blood dyscrasias —	diarrhea	hyperthyroidism
see CONTRAINDICATIONS	elevated temperature	poor nutritional state
cancer	hepatic disorders	steatorrhea
collagen vascular disease	infectious hepatitis	vitamin K deficiency
congestive heart failure	jaundice

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C Protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 8: Clinically Significant Drug Interactions with LANTUS
Drugs That May Increase the Risk of Hypoglycemia
Drugs:	Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics.
Intervention:	Dose reductions and increased frequency of glucose monitoring may be required when LANTUS is co-administered with these drugs.
Drugs That May Decrease the Blood Glucose Lowering Effect of LANTUS
Drugs:	Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones
Intervention:	Dose increases and increased frequency of glucose monitoring may be required when LANTUS is co-administered with these drugs.
Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of LANTUS
Drugs:	Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.
Intervention:	Dose adjustment and increased frequency of glucose monitoring may be required when LANTUS is co-administered with these drugs.
Drugs That May Blunt Signs and Symptoms of Hypoglycemia
Drugs:	beta-blockers, clonidine, guanethidine, and reserpine
Intervention:	Increased frequency of glucose monitoring may be required when LANTUS is co-administered with these drugs.

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Factors	Dosage Adjustments for Aripiprazole
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
Known CYP2D6 Poor Metabolizersand strong CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors	Administer half of usual dose
Strong CYP2D6 and CYP3A4inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double usual dose over 1 to 2 weeks

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
*Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	C_m _a _x
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing.
	20 mg/day	4 mg/day	1.6	-	Do not exceed 8 mg/day
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers)
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

Table name:

Intervention:	Monitor patients with concomitant use of naproxen with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	Concomitant use of naproxen and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	• During concomitant use of naproxen and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention	During concomitant use of naproxen with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).

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Table 7: Summary of AED Interactions with Oxcarbazepine
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400 to 2000	900	nc nc denotes a mean change of less than 10%	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100 to 150	600 to 1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250 to 500	600 to 1800 >1200 to 2400	nc ^, Pediatrics up to 40% increase Mean increase in adults at high oxcarbazepine doses [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400 to 2800	600 to 1800	nc	18% decrease [CI: 13% decrease, 40% decrease]

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Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
*Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	C_max
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing.
	20 mg/day	4 mg/day	1.6	-	Do not exceed 8 mg/day
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers)
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

Table name: Clinical Impact: Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of indomethacin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions ( 5.11 )]. Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions ( 5.2 ) ]. Intervention: Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions ( 5.11 )].Indomethacin is not a substitute for low dose aspirin for cardiovascular protection. Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: During concomitant use of indomethacin capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.During concomitant use of indomethacin capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions ( 5.6 )].When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.It has been reported that the addition of triamterene to a maintenance schedule of Indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together.Both indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently [ see Warnings and Precautions ( 5.6 )]. Intervention: Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels. [ see Warnings and Precautions ( 5.6 )]. Clinical Impact: The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels. Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity. Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity. Clinical Impact: Concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine's nephrotoxicity. Intervention: During concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function. Clinical Impact: Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions ( 5.2 )]. Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin [see Clinical Pharmacology ( 12.3 )].In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage. Intervention: The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended. Clinical Impact: Concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. Clinical Impact: When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased. Intervention: During the concomitant use of indomethacin and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments.


Drugs That Interfere with Hemostasis




Aspirin




ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers




Diuretics






Digoxin






Lithium






Methotrexate






Cyclosporine






NSAIDs and Salicylates






Pemetrexed






Probenecid

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Table 3: Clinically Significant Drug Interactions with Celecoxib
Drugs That Interfere w ith Hemostasis
Clinical Impact:	Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of Celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of celecoxib with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11) ].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2) ]. In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200 to 400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100 to 325 mg).
Intervention:	Concomitant use of celecoxib and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11) ]. Celecoxib is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of celecoxib and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of celecoxib and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6) ]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of celecoxib with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6) ].
Digoxin
Clinical Impact:	The concomitant use of Celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of celecoxib and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of celecoxib and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Celecoxib has no effect on methotrexate pharmacokinetics.
Intervention:	During concomitant use of celecoxib and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of celecoxib and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of celecoxib and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs a nd Salicylates
Clinical Impact:	Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2) ].
Intervention:	The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of celecoxib and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of celecoxib and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or inducers
Clinical Impact:	Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib.
Intervention	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [see Clinical Pharmacology (12.3) ].
CYP2D6 substrates
Clinical Impact:	In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs.
Intervention	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [see Clinical Pharmacology (12.3) ].
Corticosteroids
Clinical Impact:	Concomitant use of corticosteroids with celecoxib may increase the risk of GI ulceration or bleeding.
Intervention	Monitor patients with concomitant use of celecoxib with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2) ].

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)	Do not exceed 40 mg atorvastatin daily

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Table 13 Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine concentrations approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine and epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
	? Carbamazepine epoxide	May increase Carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
	? valproate	There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 7: Summary of AED Interactions with Oxcarbazepine
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400 to 2000	900	ncnc denotes a mean change of less than 10%	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100 to 150	600 to 1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250 to 500	600 to 1800 >1200 to 2400	nc ^, Pediatrics up to 40% increaseMean increase in adults at high oxcarbazepine doses [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400 to 2800	600 to 1800	nc	18% decrease [CI: 13% decrease, 40% decrease]

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Drug	Effect
Phenylephrine with prior administration of monoamine oxidase inhibitors (MAOI).	Cardiac pressor response potentiated. May cause acute hypertensive crisis.
Phenylephrine with tricyclic antidepressants.	Pressor response increased.
Phenylephrine with ergot alkaloids.	Excessive rise in blood pressure.
Phenylephrine with bronchodilator sympathomimetic agents and with epinephrine or other sympathomimetics.	Tachycardia or other arrhythmias may occur.
Phenylephrine with atropine sulfate.	Reflex bradycardia blocked; pressor response enhanced.
Phenylephrine with prior administration of propranolol or other ß-adrenergic blockers.	Cardiostimulating effects blocked.
Phenylephrine with prior administration of phentolamine or other α-adrenergic blockers.	Pressor response decreased.
Phenylephrine with diet preparations, such as amphetamines or phenylpropanolamine.	Synergistic adrenergic response.

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin	Monitor phenytoin level (7)
Methotrexate	Monitor for methotrexate toxicity (7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin tablets absorption. Take 2 hours before or 6 hours after ciprofloxacin tablets (7)

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Table 8: Selected Drug Interactions in Adults
Concomitant Drug Class: Drug Name	Effect on Concentration of Raltegravir	Clinical Comment
Metal-Containing Antacids
aluminum and/or magnesium-containing antacids	↓	Coadministration or staggered administration of aluminum and/or magnesium hydroxide-containing antacids and ISENTRESS is not recommended.
Other Agents
rifampin	↓	The recommended dosage of ISENTRESS is 800 mg twice daily during coadministration with rifampin. There are no data to guide co-administration of ISENTRESS with rifampin in patients below 18 years of age [see Dosage and Administration (2.1)].

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Table 8: Clinically Significant Drug Interactions with Clarithromycin
Drugs That Are Affected By Clarithromycin
Drug(s) with Pharmacokinetics Affected by Clarithromycin	Recommendation	Comments
Antiarrhythmics: Disopyramide Quinidine Dofetilide Amiodarone Sotalol Procainamide Digoxin	Not Recommended Use With Caution	Disopyramide, Quinidine: There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs [see Warnings and Precautions (5.3)]. Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine. There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide. Digoxin: Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are coadministered, inhibition of Pgp by clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range.
Oral Anticoagulants: Warfarin	Use With Caution	Oral anticoagulants: Spontaneous reports in the postmarketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously [see Warnings and Precautions (5.4)].
Antiepileptics: Carbamazepine	Use With Caution	Carbamazepine: Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered. Increased serum concentrations of carbamazepine were observed in clinical trials with clarithromycin. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with carbamazepine.
Antifungals: Itraconazole Fluconazole	Use With Caution No Dose Adjustment	Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly (see also Itraconazole under “Drugs That Affect Clarithromycin” in the table below). Clarithromycin may increase the plasma concentrations of itraconazole. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions. Fluconazole: [see Pharmacokinetics (12.3)]
Anti-Gout Agents: Colchicine (in patients with renal or hepatic impairment) Colchicine (in patients with normal renal and hepatic function)	Contraindicated Use With Caution	Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. The dose of colchicine should be reduced when coadministered with clarithromycin in patients with normal renal and hepatic function [see Contraindications (4.4) and Warnings and Precautions (5.4)].
Antipsychotics: Pimozide Quetiapine	Contraindicated	Pimozide: [see Contraindications (4.2)] Quetiapine: Quetiapine is a substrate for CYP3A4, which is inhibited by clarithromycin. Coadministration with clarithromycin could result in increased quetiapine exposure and possible quetiapine related toxicities. There have been postmarketing reports of somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation during concomitant administration. Refer to quetiapine prescribing information for recommendations on dose reduction if coadministered with CYP3A4 inhibitors such as clarithromycin.
Antispasmodics: Tolterodine (patients deficient in CYP2D6 activity)	Use With Caution	Tolterodine: The primary route of metabolism for tolterodine is via CYP2D6. However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when coadministered with clarithromycin.
Antivirals: Atazanavir Saquinavir (in patients with decreased renal function) Ritonavir Etravirine Maraviroc Boceprevir (in patients with normal renal function) Didanosine Zidovudine	Use With Caution No Dose Adjustment	Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)]. Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction (see Saquinavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)]. Ritonavir, Etravirine: (see Ritonavir and Etravirine under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)]. Maraviroc: Clarithromycin may result in increases in maraviroc exposures by inhibition of CYP3A metabolism. See Selzentry^® prescribing information for dose recommendation when given with strong CYP3A inhibitors such as clarithromycin. Boceprevir: Both clarithromycin and boceprevir are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when coadministered. No dose adjustments are necessary for patients with normal renal function (see Victrelis^® prescribing information). Zidovudine: Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Administration of clarithromycin and zidovudine should be separated by at least two hours [see Pharmacokinetics (12.3)]. The impact of coadministration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated.
Calcium Channel Blockers: Verapamil Amlodipine Diltiazem Nifedipine	Use With Caution	Verapamil: Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, [see Warnings and Precautions (5.4)]. Amlodipine, Diltiazem: [see Warnings and Precautions (5.4)] Nifedipine: Nifedipine is a substrate for CYP3A. Clarithromycin and other macrolides are known to inhibit CYP3A. There is potential of CYP3A-mediated interaction between nifedipine and clarithromycin. Hypotension and peripheral edema were observed when clarithromycin was taken concomitantly with nifedipine [see Warnings and Precautions (5.4)].
Ergot Alkaloids: Ergotamine Dihydroergotamine	Contraindicated	Ergotamine, Dihydroergotamine: Postmarketing reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4.6)].
Gastroprokinetic Agents: Cisapride	Contraindicated	Cisapride: [see Contraindications (4.2)]
HMG-CoA Reductase Inhibitors: Lovastatin Simvastatin Atorvastatin Pravastatin Fluvastatin	Contraindicated Use With Caution No Dose Adjustment	Lovastatin, Simvastatin, Atorvastatin, Pravastatin, Fluvastatin: [see Contraindications (4.5) and Warnings and Precautions (5.4)]
Hypoglycemic Agents: Nateglinide Pioglitazone Repaglinide Rosiglitazone Insulin	Use With Caution	Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone: [see Warnings and Precautions (5.4) and Adverse Reactions (6.2)] Insulin: [see Warnings and Precautions (5.4) and Adverse Reactions (6.2)]
Immunosuppressants: Cyclosporine Tacrolimus	Use With Caution	Cyclosporine: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine. Tacrolimus: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with tacrolimus.
Phosphodiesterase inhibitors: Sildenafil Tadalafil Vardenafil	Use With Caution	Sildenafil, Tadalafil, Vardenafil: Each of these phosphodiesterase inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant administration of clarithromycin. Coadministration of clarithromycin with sildenafil, tadalafil, or vardenafil will result in increased exposure of these phosphodiesterase inhibitors. Coadministration of these phosphodiesterase inhibitors with clarithromycin is not recommended. Increased systemic exposure of these drugs may occur with clarithromycin; reduction of dosage for phosphodiesterase inhibitors should be considered (see their respective prescribing information).
Proton Pump Inhibitors: Omeprazole	No Dose Adjustment	Omeprazole: The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when coadministered with clarithromycin as a result of increased omeprazole exposures [see Pharmacokinetics (12.3)] (see also Omeprazole under “Drugs That Affect Clarithromycin” in the table below).
Xanthine Derivatives: Theophylline	Use With Caution	Theophylline: Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations [see Pharmacokinetics (12.3)]. Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range.
Triazolobenzodiazepines and Other Related Benzodiazepines: Midazolam Alprazolam Triazolam Temazepam Nitrazepam Lorazepam	Use With Caution No Dose Adjustment	Midazolam: When oral midazolam is coadministered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated [see Warnings and Precautions (5.4) and Pharmacokinetics (12.3)]. Triazolam, Alprazolam: Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is coadministered with clarithromycin. There have been postmarketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested. In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines. Temazepam, Nitrazepam, Lorazepam: For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.
Cytochrome P450 Inducers: Rifabutin	Use With Caution	Rifabutin: Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis (see Rifabutin under “Drugs That Affect Clarithromycin” in the table below).
Other Drugs Metabolized by CYP3A: Alfentanil Bromocriptine Cilostazol Methylprednisole Vinblastine Phenobarbital St. John’s Wort	Use With Caution	There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort.
Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A: Hexobarbital Phenytoin Valproate	Use With Caution	There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.
Drugs that Affect Clarithromycin
Drug(s) that Affect the Pharmacokinetics of Clarithromycin	Recommendation	Comments
Antifungals: Itraconazole	Use With Caution	Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions (see also Itraconazole under “Drugs That Are Affected By Clarithromycin” in the table above).
Antivirals: Atazanavir Ritonavir (in patients with decreased renal function) Saquinavir (in patients with decreased renal function) Etravirine Saquinavir (in patients with normal renal function) Ritonavir (in patients with normal renal function)	Use With Caution No Dose Adjustments	Atazanavir: When clarithromycin is coadministered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology (12.3)]. Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is coadministered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex. Doses of clarithromycin greater than 1000 mg per day should not be coadministered with protease inhibitors. Ritonavir: Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is coadministered with ritonavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium [see Pharmacokinetics (12.3)]. Doses of clarithromycin greater than 1000 mg per day should not be coadministered with protease inhibitors. Saquinavir: When saquinavir is coadministered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (refer to ritonavir above) [see Pharmacokinetics (12.3)]. Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.
Proton Pump Inhibitors: Omeprazole	Use With Caution	Omeprazole: Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole [see Pharmacokinetics (12.3)].
Miscellaneous Cytochrome P450 Inducers: Efavirenz Nevirapine Rifampicin Rifabutin Rifapentine	Use With Caution	Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are Affected By Clarithromycin” in the table above).

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Table 7 Summary of AED Interactions with Oxcarbazepine Tablets, USP
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Tablets Dose (mg/day)	Influence of Oxcarbazepine Tablets on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400-2000	900	nc nc denotes a mean change of less than 10%	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100-150	600-1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250-500	600-1800 >1200-2400	nc ^, Pediatrics up to 40% increase Mean increase in adults at high oxcarbazepine tablets, USP doses [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400-2800	600-1800	nc	18% decrease [CI: 13% decrease, 40% decrease]

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion–the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide(including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T ₄ and T ₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide(including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT ₄. Continued administration results in a decrease in serum T ₄, and normal FT ₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T ₄ and T ₃ to TBG and transthyretin. An initial increase in serum FT ₄ is followed by return of FT ₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T ₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T ₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5’-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T ₄ to T ₃, leading to decreased T ₃ levels. However, serum T ₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T ₃ and T ₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T ₃ concentrations by 30% with minimal change in serum T ₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T ₃ and T ₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.

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Drugs that Affect Renal Function	A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics	Dofetilide	Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
	Sotalol	Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
	Dronedarone	Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog	Teriparatide	Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement	Thyroid Supplement	Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics	Epinephrine Norepinephrine Dopamine	Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents	Succinylcholine	May cause sudden extrusion of potassium from muscle cells causing arrhythmias inpatients taking digoxin.
Supplements	Calcium	If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers		Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.
Hyperpolarization-activated cyclic nucleotide-gated channel blocker	Ivabradine	Can increase the risk of bradycardia.

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Concomitant Drug Name	Effect of Carbamazepine on Other Drugs	Clinical Recommendation
Boceprevir	Decrease in boceprevir levels	Coadministration of carbamazepine with boceprevir is contraindicated
Acetaminophen, albendazole, alprazolam, aprepitant, buprenorphone, bupropion, citalopram, clonazepam, clozapine, corticosteroids (e.g., prednisolone, dexamethasone), cyclosporine, dicumarol, dihydropyridine calcium channel blockers (e.g., felodipine), doxycycline, ethosuximide, everolimus, haloperidol, imatinib, itraconazole, lamotrigine, levothyroxine, methadone, methsuximide, mianserin, midazolam, olanzapine, oral and other hormonal contraceptives, oxcarbazepine, paliperidone, phensuximide, phenytoin, praziquantel, protease inhibitors, risperidone, sertraline, sirolimus, tadalafil, theophylline, tiagabine, topiramate, tramadol, trazodone, tricyclic antidepressants (e.g., imipramine, amitriptyline, nortriptyline), valproate, warfarin, ziprasidone, zonisamide	Decrease in concomitant drug levels	Monitor the concentration and consider a dosage adjustment of the concomitant drug(s)
Cyclophosphamide	Increase in cyclo-phosphamide levels (potential for increased toxicity)	Monitor for signs of increased cyclophosphamide toxicity
Aripiprazole	Decrease in aripiprazole levels	When carbamazepine is added to aripiprazole, the aripiprazole dose should be doubled; additional dose increases should be based on clinical evaluation; when carbamazepine is withdrawn from the combination therapy, the aripiprazole dose should be reduced
Tacrolimus	Decrease in tacrolimus levels	Monitor tacrolimus blood concentrations and make appropriate dosage adjustments
Temsirolimus	Decrease in temsirolimus levels	The use of concomitant strong CYP3A4 inducers such as carbamazepine should be avoided with temsirolimus; if carbamazepine must be coadministered with temsirolimus, consider adjusting the dosage of temsirolimus
Lapatinib	Decrease in lapatinib levels	The use of carbamazepine with lapatinib should generally be avoided; dosage adjustment should be considered if lapatinib is coadministered with carbamazepine; if carbamazepine is started in a patient already taking lapatinib, the dose of lapatinib should be gradually titrated up; if carbamazepine is discontinued, the lapatinib dose should be reduced
Nefazodone	Decrease in nefazodone levels	Coadministration of carbamazepine with nefazodone is contraindicated
Valproate	Decrease in valproate levels	Monitor valproate concentrations when carbamazepine is introduced or withdrawn in patients using valproic acid

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of aripiprazole with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.8)].
Benzodiazepines(e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.8)].	Monitor sedation and blood pressure. Adjust dose accordingly.

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Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C_max and AUCτ)	Recommendations for Drug Dosage Adjustment/Comments
Sirolimus* (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin* (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (400 mg q 24h) (CYP3A4 Inhibition) Efavirenz (300 mg q 24h) (CYP3A4 Inhibition)	Significantly Increased Slight Increased in AUC_t	Contraindicated When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)(CYP3A4 Inhibition) Low-dose Ritonavir (100 mg q12h)	No Significant Effect of Voriconazole on Ritonavir C_max or AUCτ Slight Decrease in Ritonavir C_max and AUCτ	Contraindicated because of significant reduction of voriconazole C_max and AUCτ
		Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole C_max and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated
Cyclosporine* (CYP3A4 Inhibition)	AUCτ Significantly Increased; No Significant Effect on C_max	When initiating therapy with voriconazole in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
Methadone*** (CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see DRUG INTERACTIONS (7)]
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see DRUG INTERACTIONS (7)].
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see DRUG INTERACTIONS (7)].
NSAIDs**** including ibuprofen and diclofenac (CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed. [see DRUG INTERACTIONS (7)].
Tacrolimus* (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with voriconazole in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin* (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)**	Increased	Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin* (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	Monitor PT or other suitable anticoagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole* (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with voriconazole in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects on Indinavir Exposure	No dosage adjustment for indinavir when coadministered with voriconazole tablets
	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIs***** (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.
Everolimus (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Concomitant administration of voriconazole and everolimus is not recommended

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Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir )	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table II. Clinically Significant Drug Interactions With Theophylline*
Drug	Type Of Interaction	Effect**
* Refer to PRECAUTIONS , Drug Interactions for further information regarding table. ** Average effect on steady-state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine	Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.
Alcohol	A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours.	30% increase
Allopurinol	Decreases theophylline clearance at allopurinol doses ≥600 mg/day.	25% increase
Aminoglutethimide	Increases theophylline clearance by induction of microsomal enzyme activity.	25% decrease
Carbamazepine	Similar to aminoglutethimide.	30% decrease
Cimetidine	Decreases theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase
Ciprofloxacin	Similar to cimetidine.	40% increase
Clarithromycin	Similar to erythromycin.	25% increase
Diazepam	Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.	Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram	Decreases theophylline clearance by inhibiting hydroxylation and demethylation.	50% increase
Enoxacin	Similar to cimetidine.	300% increase
Ephedrine	Synergistic CNS effects.	Increased frequency of nausea, nervousness, and insomnia.
Erythromycin	Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen	Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.	30% increase
Flurazepam	Similar to diazepam.	Similar to diazepam.
Fluvoxamine	Similar to cimetidine.	Similar to cimetidine.
Halothane	Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.	Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A	Decreases theophylline clearance.	100% increase
Isoproterenol (I.V.)	Increases theophylline clearance.	20% decrease
Ketamine	Pharmacologic	May lower theophylline seizure threshold.
Lithium	Theophylline increases renal lithium clearance.	Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam	Similar to diazepam.	Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.	20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine	Similar to disulfiram.	80% increase
Midazolam	Similar to diazepam.	Similar to diazepam.
Moricizine	Increases theophylline clearance.	25% decrease
Pancuronium	Theophylline may antagonize nondepolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.	Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline	Decreases theophylline clearance.	30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.	25% decrease after two weeks of concurrent Phenobarbital.
Phenytoin	Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.	Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone	Decreases theophylline clearance and pharmacologic interaction.	40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and pharmacologic interaction.	100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin	Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.	20 - 40% decrease
Sulfinpyrazone	Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.	20% decrease
Tacrine	Similar to cimetidine, also increases renal clearance of theophylline.	90% increase
Thiabendazole	Decreases theophylline clearance.	190% increase
Ticlopidine	Decreases theophylline clearance.	60% increase
Troleandomycin	Similar to erythromycin.	33 - 100% increase depending on troleandomycin dose.
Verapamil	Similar to disulfiram.	20% increase

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Table 1: Oral drugs that can be administered concomitantly with Auryxia
Amlodipine Aspirin Atorvastatin Calcitriol Clopidogrel Digoxin Diltiazem Doxercalciferol Enalapril Fluvastatin Glimepiride Levofloxacin Losartan Metoprolol Pravastatin Propranolol Sitagliptin Warfarin
Oral drugs that have to be separated from Auryxia and meals
	Dosing Recommendations
Doxycycline	Take at least 1 hour before Auryxia
Ciprofloxacin	Take at least 2 hours before or after Auryxia

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Drugs That Interfere with Hemostasis
Clinical Impact:	Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of celecoxib capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions (5.11) ].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions (5.2) ]. In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200-400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100-325 mg).
Intervention:	Concomitant use of celecoxib capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions (5.11) ]. Celecoxib capsules is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of celecoxib capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of celecoxib capsules and ACE-inhibitors or ARBs in patients who are elderly, volume- depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions (5.6) ]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of celecoxib capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see Warnings and Precautions (5.6) ].
Digoxin
Clinical Impact:	The concomitant use of celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of celecoxib capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of celecoxib capsules and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Celecoxib capsules have no effect on methotrexate pharmacokinetics.
Intervention:	During concomitant use of celecoxib capsules and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of celecoxib capsules and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of celecoxib capsules and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions (5.2) ].
Intervention:	The concomitant use of celecoxib with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of celecoxib capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of celecoxib capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or inducers
Clinical Impact:	Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib.
Intervention	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [ see Clinical Pharmacology (12.3) ].
CYP2D6 substrates
Clinical Impact:	In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs.
Intervention	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [ see Clinical Pharmacology (12.3) ].
Corticosteroids
Clinical Impact:	Concomitant use of corticosteroids with celecoxib capsules may increase the risk of GI ulceration or bleeding.
Intervention	Monitor patients with concomitant use of celecoxib capsules with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)].

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Table 5. Established Drug Interactions Based on Drug Interaction Trials
Concomitant Drug Class: Drug Name	Effect on Concentration	Clinical Comments
ANGIOTENSIN RECEPTOR BLOCKERS
valsartan^* losartan^* candesartan^*	↑ angiotensin receptor blockers	Decrease the dose of the angiotensin receptor blockers and monitor patients for signs and symptoms of hypotension and/or worsening renal function. If such events occur, consider further dose reduction of the angiotensin receptor blocker or switching to an alternative to the angiotensin receptor blocker.
ANTIARRHYTHMICS
amiodarone^, bepridil^, disopyramide^, flecainide^, lidocaine (systemic)^, mexiletine^, propafenone^, quinidine^	↑ antiarrhythmics	Contraindicated antiarrhythmics [see Contraindications (4)]. Therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with VIEKIRA XR.
ANTIDIABETIC DRUGS
metformin	↔ metformin	Monitor for signs of onset of lactic acidosis such as respiratory distress, somnolence, and non-specific abdominal distress or worsening renal function. Concomitant metformin use in patients with renal insufficiency or hepatic impairment is not recommended. Refer to the prescribing information of metformin for further guidance.
ANTIFUNGALS
ketoconazole	↑ ketoconazole	When VIEKIRA XR is co-administered with ketoconazole, the maximum daily dose of ketoconazole should be limited to 200 mg per day.
voriconazole^*	↓ voriconazole	Co-administration of VIEKIRA XR with voriconazole is not recommended unless an assessment of the benefit-to-risk ratio justifies the use of voriconazole.
ANTIPSYCHOTIC
quetiapine^*	↑ quetiapine	Contraindicated antipsychotics [see Contraindications (4)]. Quetiapine: Initiation of VIEKIRA XR in patients taking quetiapine: Consider alternative anti-HCV therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6^th of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for the recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking VIEKIRA XR: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
CALCIUM CHANNEL BLOCKERS
amlodipine nifedipine^* diltiazem^* verapamil^*	↑ calcium channel blockers	Decrease the dose of the calcium channel blocker. The dose of amlodipine should be decreased by at least 50%. Clinical monitoring of patients is recommended for edema and/or signs and symptoms of hypotension. If such events occur, consider further dose reduction of the calcium channel blocker or switching to an alternative to the calcium channel blocker.
CORTICOSTEROIDS (INHALED/NASAL)
fluticasone^*	↑ fluticasone	Concomitant use of VIEKIRA XR with inhaled or nasal fluticasone may reduce serum cortisol concentrations. Alternative corticosteroids should be considered, particularly for long term use.
DIURETICS
furosemide	↑ furosemide (C_max)	Clinical monitoring of patients is recommended and therapy should be individualized based on patient’s response.
ANTIRETROVIRAL AGENTS: PROTEASE INHIBITORS
atazanavir/ritonavir once daily	↑ paritaprevir	When coadministered with VIEKIRA XR, atazanavir 300 mg (without ritonavir) should only be given in the morning.
darunavir/ritonavir	↓ darunavir (C_trough)	Treatment naïve patients or treatment experienced patients with no darunavir associated substitutions: Darunavir 800 mg once daily (without ritonavir) can be co-administered with VIEKIRA XR. Treatment experienced patients with at least one darunavir resistance associated substitution or with no baseline resistance information: Co-administration of darunavir/ritonavir 600/100 mg twice daily with VIEKIRA XR is not recommended.
lopinavir/ritonavir	↑ paritaprevir	Co-administration of VIEKIRA XR with lopinavir/ritonavir is not recommended.
ANTIRETROVIRAL AGENTS: NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
rilpivirine	↑ rilpivirine	Contraindicated non-nucleoside reverse transcriptase inhibitors [see Contraindications (4)]. Rilpivirine: Co-administration of VIEKIRA XR with rilpivirine once daily is not recommended due to potential for QT interval prolongation with higher concentrations of rilpivirine.
HMG CoA REDUCTASE INHIBITORS:
pravastatin rosuvastatin	↑ pravastatin ↑ rosuvastatin	Contraindicated HMG CoA Reductase Inhibitors [see Contraindications (4)]. Rosuvastatin: Dose of rosuvastatin should not exceed 10 mg per day. Pravastatin: Dose of pravastatin should not exceed 40 mg per day.
IMMUNOSUPPRESSANTS
cyclosporine	↑ cyclosporine	For contraindicated immunosuppressants [see Contraindications (4)]. When initiating therapy with VIEKIRA XR, reduce cyclosporine dose to 1/5^th of the patient’s current cyclosporine dose. Measure cyclosporine blood concentrations to determine subsequent dose modifications. Upon completion of VIEKIRA XR therapy, the appropriate time to resume pre-VIEKIRA XR dose of cyclosporine should be guided by assessment of cyclosporine blood concentrations. Frequent assessment of renal function and cyclosporine-related side effects is recommended.
LONG ACTING BETA-ADRENOCEPTOR AGONIST
salmeterol^*	↑ salmeterol	Concurrent administration of VIEKIRA XR and salmeterol is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
MUSCLE RELAXANTS
carisoprodol	↓ carisoprodol ↔ mepobramate (metabolite of carisoprodol)	Increase dose if clinically indicated.
cyclobenzaprine	↓cyclobenzaprine ↓norcyclobenzaprine (metabolite of cyclobenzaprine)	Increase dose if clinically indicated.
NARCOTIC ANALGESICS
acetaminophen/hydrocodone	↑ hydrocodone ↔ acetaminophen	Reduce the dose of hydrocodone by 50% and monitor patients for respiratory depression and sedation at frequent intervals. Upon completion of VIEKIRA XR therapy, adjust the hydrocodone dose and monitor for signs of opioid withdrawal.
buprenorphine/naloxone	↑ buprenorphine ↑ norbuprenorphine (metabolite of buprenorphine)	Patients should be closely monitored for sedation and cognitive effects.
PROTON PUMP INHIBITORS
omeprazole	↓ omeprazole	Monitor patients for decreased efficacy of omeprazole. Consider increasing the omeprazole dose in patients whose symptoms are not well controlled; avoid use of more than 40 mg per day of omeprazole.
SEDATIVES/HYPNOTICS
alprazolam	↑ alprazolam	Contraindicated Sedatives/Hypnotics [see Contraindications (4)]. Alprazolam: Clinical monitoring of patients is recommended. A decrease in alprazolam dose can be considered based on clinical response.
diazepam	↓ diazepam ↓ nordiazepam (metabolite of diazepam)	Increase dose if clinically indicated.
See Clinical Pharmacology, Tables 7 and 8 . The direction of the arrow indicates the direction of the change in exposures (C_max and AUC) (↑ = increase of more than 20%, ↓ = decrease of more than 20%, ↔ = no change or change less than 20%). ^*not studied.

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Antiretrovirals
Clinical Impact:	The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. • Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3)]. • Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)]. • There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
Intervention:	Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications (4)]. Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:	Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention:	Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact:	Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].
Intervention:	A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact:	Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)]. There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention:	Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6)].
Citalopram
Clinical Impact:	Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention:	Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:	Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].
Intervention:	Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:	Potential for increased exposure of phenytoin.
Intervention:	Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:	Increased exposure of diazepam [see Clinical Pharmacology (12.3)].
Intervention:	Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:	Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention:	Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:	Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:	Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)]. See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:	Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:	See Contraindications, Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact:	Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention:	Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:	Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10),Clinical Pharmacology (12.2)].
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:	Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact:	There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:	An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:	There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:	Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.

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AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Figure 1: Effect of interacting drugs on the pharmacokinetics of venlafaxine and active metabolite O-desmethylvenlafaxine (ODV).

Abbreviations: ODV, O-desmethylvenlafaxine; AUC, area under the curve; Cmax, peak plasma concentrations; EM's, extensive metabolizers; PM's, poor metabolizers * No dose adjustment on co-administration with CYP2D6 inhibitors (Fig 3 and Metabolism Section 12.3)

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Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, Posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine,danazol	Contraindicated with simvastatin
Verapamil, diltiazem	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T ₄ and T ₃levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT ₄ . Continued administration results in a decrease in serum T ₄ and normal FT ₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T ₄ and T ₃ to TBG and transthyretin. An initial increase in serum FT ₄ is followed by return of FT ₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T ₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T ₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T ₄ to T ₃, leading to decreased T ₃ levels. However, serum T ₄levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T ₃ and T ₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T ₃concentrations by 30% with minimal change in serum T ₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T ₃ and T ₄levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³ I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours (two times the recommended twice daily dose) in healthy volunteers (n=24)
Concomitant Drug	C_maxSS (Peak plasma concentration)	AUC_ss(0–12h) (Extent of systemic exposure)
Erythromycin (500 mg every 8 hrs)	+82%	+109%
Ketoconazole (400 mg once daily)	+135%	+164%

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^a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
^b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Table II. Clinically significant drug interactions with theophylline^*.
Drug	Type of Interaction	Effect^**
^* Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
^** Average effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine	Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.
Alcohol	A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours.	30% increase
Allopurinol	Decreases theophylline clearance at allopurinol doses ≥600 mg/day.	25% increase
Aminoglutethimide	Increases theophylline clearance by induction of microsomal enzyme activity.	25% decrease
Carbamazepine	Similar to aminoglutethimide.	30% decrease
Cimetidine	Decreases theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase
Ciprofloxacin	Similar to cimetidine.	40% increase
Clarithromycin	Similar to erythromycin.	25% increase
Diazepam	Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.	Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram	Decreases theophylline clearance by inhibiting hydroxylation and demethylation.	50% increase
Enoxacin	Similar to cimetidine.	300% increase
Ephedrine	Synergistic CNS effects.	Increased frequency of nausea, nervousness, and insomnia.
Erythromycin	Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen	Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.	30% increase
Flurazepam	Similar to diazepam.	Similar to diazepam.
Fluvoxamine	Similar to cimetidine.	Similar to cimetidine.
Halothane	Halothane sensitizes the myocardium. to catecholamines, theophylline increases release of endogenous catecholamines.	Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A	Decreases theophylline clearance.	100% increase
Isoproterenol (IV)	Increases theophylline clearance.	20% decrease
Ketamine	Pharmacologic seizure threshold.	May lower theophylline
Lithium	Theophylline increases renal lithium clearance.	Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam	Similar to diazepam.	Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.	20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine	Similar to disulfiram.	80% increase
Midazolam	Similar to diazepam.	Similar to diazepam.
Moricizine	Increases theophylline clearance.	25% decrease
Pancuronium	Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.	Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline	Decreases theophylline clearance.	30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.	25% decrease after two weeks of concurrent PB.
Phenytoin	Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.	Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone	Decreases theophylline clearance and pharmacologic interaction.	40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and pharmacologic interaction.	100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin	Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.	20-40% decrease
Sulfinpyrazone	Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.	20% decrease
Tacrine	Similar to cimetidine, also increases renal clearance of theophylline.	90% increase
Thiabendazole	Decreases theophylline clearance.	190% increase
Ticlopidine	Decreases theophylline clearance.	60% increase
Troleandomycin	Similar to erythromycin.	33-100% increase depending on troleandomycin dose.
Verapamil	Similar to disulfiram.	20% increase

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Table 12: Clinically Important Drug Interactions with SAPHRIS
Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Antihypertensive Drugs	Because of its α₁-adrenergic antagonism with potential for inducing hypotension, SAPHRIS may enhance the effects of certain antihypertensive agents [see Warnings and Precautions (5.7)].	Monitor blood pressure and adjust dosage of antihypertensive drug accordingly.
Strong CYP1A2 Inhibitors (e.g., Fluvoxamine)	SAPHRIS is metabolized by CYP1A2. Marginal increase of asenapine exposure was observed when SAPHRIS is used with fluvoxamine at 25 mg administered twice daily [see Clinical Pharmacology (12.3)]. However, the tested fluvoxamine dose was suboptimal. Full therapeutic dose of fluvoxamine is expected to cause a greater increase in asenapine exposure.	Dosage reduction for SAPHRIS based on clinical response may be necessary.
CYP2D6 substrates and inhibitors (e.g., paroxetine)	SAPHRIS may enhance the inhibitory effects of paroxetine on its own metabolism. Concomitant use of paroxetine with SAPHRIS increased the paroxetine exposure by 2-fold as compared to use paroxetine alone [see Clinical Pharmacology (12.3)].	Reduce paroxetine dose by half when paroxetine is used in combination with SAPHRIS.

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Factors	Dosage Adjustment for Aripiprazole tablets
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors	Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double usual dose over 1 to 2 weeks

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T ₄ and T ₃levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT ₄ . Continued administration results in a decrease in serum T ₄ and normal FT ₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T ₄ and T ₃ to TBG and transthyretin. An initial increase in serum FT ₄ is followed by return of FT ₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T ₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T ₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T ₄ to T ₃, leading to decreased T ₃ levels. However, serum T ₄levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T ₃ and T ₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T ₃concentrations by 30% with minimal change in serum T ₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T ₃ and T ₄levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³ I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T ₄ and T ₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT ₄. Continued administration results in a decrease in serum T ₄ and normal FT ₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T ₄ and T ₃ to TBG and transthyretin. An initial increase in serum FT ₄, is followed by return of FT ₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T ₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T ₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T ₄ to T ₃, leading to decreased T ₃ levels. However, serum T ₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T ₃ and T ₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T ₃ concentrations by 30% with minimal change in serum T ₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T ₃ and T ₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 3: Clinically Relevant Interactions Affecting Naldemedine When Co-Administered with Other Drugs
Strong CYP3A Inducers (e.g., rifampin, carbamazepine, phenytoin, St. John’s Wort)
Clinical Impact	Significant decrease in plasma naldemedine concentrations, which may reduce efficacy [see Clinical Pharmacology (12.3)]
Intervention	Avoid use of SYMPROIC with strong CYP3A inducers.
Other Opioid Antagonists
Clinical Impact	Potential for additive effect of opioid receptor antagonism and increased risk of opioid withdrawal.
Intervention	Avoid use of SYMPROIC with another opioid antagonist.
Moderate (e.g., fluconazole, atazanavir, aprepitant, diltiazem, erythromycin) and Strong (e.g., itraconazole, ketoconazole, clarithromycin, ritonavir, saquinavir) CYP3A Inhibitors
Clinical Impact	Increase in plasma naldemedine concentrations [see Clinical Pharmacology (12.3)]
Intervention	Monitor for potential naldemedine-related adverse reactions [see Adverse Reactions (6.1)].
P-glycoprotein (P-gp) Inhibitors (e.g., amiodarone, captopril, cyclosporine, quercetin, quinidine, verapamil)
Clinical Impact	Increase in plasma naldemedine concentrations [see Clinical Pharmacology (12.3)]
Intervention	Monitor for potential naldemedine-related adverse reactions [see Adverse Reactions (6.1)].

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( 7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( 7)
Phenytoin	Monitor phenytoin level ( 7)
Methotrexate	Monitor for methotrexate toxicity ( 7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine ( 7)
Multivalent cation-containing products including antacids, metal cations, or didanosine	Decreased Ciprofloxacin absorption. Take 2 hours before or 6 hours after Ciprofloxacin ( 7)

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Summary of AED interactions with topiramate (7.1).
AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400mg/day	13% decrease

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Bleeding times
Clinical Impact:	Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention:	This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact:	The administration of naproxen may result in increased urinary values for 17 ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention:	Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact:	Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention:	This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4 , 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11 , 7.3)

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Factors	Dosage Adjustments for Aripiprazole
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
Known CYP2D6 Poor Metabolizersand strong CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors	Administer half of usual dose
Strong CYP2D6 and CYP3A4inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double usual dose over 1 to 2 weeks

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine concentrations approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine and carbamazepine epoxide	? carbamazepine epoxide	May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2 fold.
Valproate	? valproate	There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)	VIAGRA 50 mg (95% CI)
Supine	9.08 (5.48, 12.68)
Standing	11.62 (7.34, 15.90)

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Table 4: Clinically Relevant Interactions Affecting Omeprazole When Co-Administered with Other Drugs
CYP2C19 or CYP3A4 Inducers
Clinical Impact:	Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention:	St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions (5.9)]. Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:	Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
Intervention:	Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole.

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Table 8: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2) ]
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.9) ].
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.11) and Use in Specific Populations (8.5) ].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs [see Adverse Reactions (6.1) ].
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anticoagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions (5.15) ].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution Two-fold increase in exposure	Monitor for sildenafil toxicity [see Clinical Pharmacology (12.3) ].
Duloxetine	Avoid Use Five-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity.
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( > 1 µg/kg/min); Glucocorticoids (hydrocortisone > 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T ₄ and T ₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT ₄. Continued administration results in a decrease in serum T ₄ and normal FT ₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T ₄ and T ₃ to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT ₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T ₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T ₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5’-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone > 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T ₄ to T ₃, leading to decreased T ₃ levels. However, serum T ₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T ₃ and T ₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T ₃ concentrations by 30% with minimal change in serum T ₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T ₃ and T ₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ⁹⁹mTc
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.

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Table 5. Established Drug Interactions Based on Drug Interaction Trials
Concomitant Drug Class: Drug Name	Effect on Concentration	Clinical Comments
ANGIOTENSIN RECEPTOR BLOCKERS e.g.
valsartan, losartan, candesartan*	↑ angiotensin receptor blockers	Decrease the dose of the angiotensin receptor blockers and monitor patients for signs and symptoms of hypotension and/or worsening renal function. If such events occur, consider further dose reduction of the angiotensin receptor blocker or switching to an alternative to the angiotensin receptor blocker.
ANTIARRHYTHMICS
digoxin	↑ digoxin	For contraindicated antiarrhythmics [see Contraindications (4)]. Decrease digoxin dose by 30-50%. Appropriate monitoring of serum digoxin levels is recommended.
amiodarone, bepridil, disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine	↑ antiarrhythmics	Therapeutic monitoring (if available) is recommended for antiarrhythmics when co-administered with TECHNIVIE.
ANTIDIABETIC DRUGS
metformin	↔ metformin	Monitor for signs of onset of lactic acidosis such as respiratory distress, somnolence, and non-specific abdominal distress or worsening renal function. Concomitant metformin use in patients with renal insufficiency or hepatic impairment is not recommended. Refer to the prescribing information of metformin for further guidance.
ANTIFUNGALS
ketoconazole	↑ ketoconazole	When TECHNIVIE is co-administered with ketoconazole, the maximum daily dose of ketoconazole should be limited to 200 mg per day.
voriconazole*	↓ voriconazole	Co-administration of TECHNIVIE with voriconazole is not recommended unless an assessment of the benefit-to-risk ratio justifies the use of voriconazole.
ANTIPSYCHOTICS
quetiapine*	↑ quetiapine	For contraindicated antipsychotics [see Contraindications (4)]. Initiation of TECHNIVIE in patients taking quetiapine: Consider alternative anti-HCV therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6^th of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking TECHNIVIE: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
CALCIUM CHANNEL BLOCKERS
amlodipine, nifedipine, diltiazem, verapamil*	↑ calcium channel blockers	Decrease the dose of the calcium channel blocker. The dose of amlodipine should be decreased by at least 50%. Clinical monitoring of patients is recommended for edema and/or signs and symptoms of hypotension. If such events occur, consider further dose reduction of the calcium channel blocker or switching to an alternative to the calcium channel blocker.
CORTICOSTEROIDS (INHALED/NASAL)
fluticasone*	↑ fluticasone	Concomitant use of TECHNIVIE with inhaled or nasal fluticasone may reduce serum cortisol concentrations. Alternative corticosteroids should be considered, particularly for long term use.
DIURETICS
furosemide	↑ furosemide (C_max)	Clinical monitoring of patients is recommended and therapy should be individualized based on patient’s response.
HIV-ANTIVIRAL AGENTS
atazanavir or atazanavir/ritonavir	↑ paritaprevir	Co-administration of TECHNIVIE with atazanavir or atazanavir/ritonavir is not recommended.
darunavir/ritonavir	↓ darunavir (C_trough)	Treatment naïve patients or treatment experienced patients with no darunavir-associated mutations: Darunavir 800 mg once daily (without ritonavir) can be co-administered with TECHNIVIE.
lopinavir/ritonavir	↑ paritaprevir	Co-administration of TECHNIVIE with lopinavir/ritonavir is not recommended.
rilpivirine	↑ rilpivirine	For contraindicated non-nucleoside reverse transcriptase inhibitors [see Contraindications (4)]. Co-administration of TECHNIVIE with rilpivirine once daily is not recommended due to potential for QT interval prolongation with higher concentrations of rilpivirine.
HMG CoA REDUCTASE INHIBITORS
pravastatin	↑ pravastatin	For contraindicated HMG CoA Reductase Inhibitors [see Contraindications (4)]. When TECHNIVIE is co-administered with pravastatin, the dose of pravastatin should not exceed 40 mg per day.
IMMUNOSUPPRESSANTS
cyclosporine	↑ cyclosporine	For contraindicated immunosuppressants [see Contraindications (4)]. When initiating therapy with TECHNIVIE, reduce cyclosporine dose to 1/5^th of the patient’s current cyclosporine dose. Measure cyclosporine blood concentrations to determine subsequent dose modifications. Upon completion of TECHNIVIE therapy, the appropriate time to resume pre-TECHNIVIE dose of cyclosporine should be guided by assessment of cyclosporine blood concentrations. Frequent assessment of renal function and cyclosporine-related side effects is recommended.
LONG ACTING BETA-ADRENOCEPTOR AGONIST
salmeterol*	↑ salmeterol	Concurrent administration of TECHNIVIE and salmeterol is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
MUSCLE RELAXANTS
carisoprodol	↓ carisoprodol ↔ mepobramate (metabolite of carisoprodol)	Increase dose if clinically indicated.
cyclobenzaprine	↓cyclobenzaprine ↓norcyclobenzaprine (metabolite of cyclobenzaprine)	Increase dose if clinically indicated.
NARCOTIC ANALGESICS
buprenorphine/naloxone	↑ buprenorphine ↑ norbuprenorphine (metabolite of buprenorphine)	Patients should be closely monitored for sedation and cognitive effects.
Hydrocodone/ acetaminophen	↑ hydrocodone ↔ acetaminophen	Reduce the dose of hydrocodone by 50% and monitor patients for respiratory depression and sedation at frequent intervals. Upon completion of TECHNIVIE therapy, adjust the hydrocodone dose and monitor for signs of opioid withdrawal.
PROTON PUMP INHIBITORS
omeprazole	↓ omeprazole	Monitor patients for decreased efficacy of omeprazole. Consider increasing the omeprazole dose in patients whose symptoms are not well controlled; avoid use of more than 40 mg per day of omeprazole.
SEDATIVES/HYPNOTICS
alprazolam	↑ alprazolam	For contraindicated Sedatives/Hypnotics [see Contraindications (4)]. Clinical monitoring of patients is recommended. A decrease in alprazolam dose can be considered based on clinical response.
diazepam	↓ diazepam ↓ nordiazepam (metabolite of diazepam)	Increase dose if clinically indicated.
*Not studied. See Clinical Pharmacology, Tables 7 and 8 . The direction of the arrow indicates the direction of the change in exposures (C_max and AUC) (↑ = increase of more than 20%, ↓ = decrease of more than 20%).

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Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
Drug Name	Effect on Concentration of Nevirapine or Concomitant Drug	Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/RitonavirThe interaction between Nevirapine and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.	↓ Atazanavir ↑ Nevirapine	Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir	↓ Amprenavir ↑ Nevirapine	Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir	↓ Amprenavir ↑ Nevirapine	No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir	↓ Indinavir	The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir	↓Lopinavir	Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra^® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir	↓Nelfinavir M8 Metabolite ↓Nelfinavir C_min	The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/ritonavir	The interaction between nevirapine and saquinavir/ritonavir has not been evaluated	The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz	↓ Efavirenz	The appropriate doses of these combinations with respect to safety and efficacy have not been established.
Delavirdine Etravirine Rilpivirine		Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.
Hepatitis C Antiviral Agents
Boceprevir	Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine.	Nevirapine and boceprevir should not be coadministered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy.
Telaprevir	Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir.	Nevirapine and telaprevir should not be coadministered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events.
Other Agents
Analgesics:
Methadone	↓ Methadone	Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics:
Amiodarone, disopyramide, lidocaine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Antibiotics: Clarithromycin	↓ Clarithromycin ↑ 14-OH clarithromycin	Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Antibiotics:
Rifabutin	↑ Rifabutin	Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin	↓ Nevirapine	Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants: Carbamazepine, clonazepam, ethosuximide	Plasma concentrations of nevirapine and the anticonvulsant may be decreased.	Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals:
Fluconazole	↑Nevirapine	Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Ketoconazole	↓ Ketoconazole	Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Itraconazole	↓ Itraconazole	Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics: Warfarin	Plasma concentrations may be increase.	Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers: Diltiazem, nifedipine, verapamil	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Cancer chemotherapy: Cyclophosphamide	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Ergot alkaloids: Ergotamine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Motility agents: Cisapride	Plasma concentrations may be decreased.	Appropriate doses for this combinations have not been established.
Opiate agonists: Fentanyl	Plasma concentrations may be decreased.	Appropriate doses for this combinations have not been established.
Oral contraceptives:
Ethinyl estradiol and Norethindrone	↓ Ethinyl estradiol ↓ Norethindrone	Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.

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NA – Not available/reported
Digoxin concentrations increased greater than 50%
	Digoxin Serum Concentration Increase	Digoxin AUC Increase	Recommendations
Amiodarone	70%	NA	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
Captopril	58%	39%
Clarithromycin	NA	70%
Dronedarone	NA	150%
Gentamicin	129-212%	NA
Erythromycin	100%	NA
Itraconazole	80%	NA
Nitrendipine	57%	15%
Propafenone	NA	60-270%
Quinidine	100%	NA
Ranolazine	50%	NA
Ritonavir	NA	86%
Tetracycline	100%	NA
Verapamil	50-75%	NA
Digoxin concentrations increased less than 50%
Atorvastatin	22%	15%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
Carvedilol	16%	14%
Diltiazem	20%	NA
Indomethacin	40%	NA
Nefazodone	27%	15%
Nifedipine	45%	NA
Propantheline	24%	24%
Quinine	NA	33%
Saquinavir	27%	49%
Spironolactone	25%	NA
Telmisartan	20-49%	NA
Tolvaptan	30%	NA
Trimethoprim	22-28%	NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole, rabeprazole,			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate, sulfasalazine			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20-40% as necessary.
No significant Digoxin exposure changes
Please refer to section 12 for a complete list of drugs which were studied but reported no significant changes on digoxin exposure.			No additional actions are required.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir )	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)	Do not exceed 40 mg atorvastatin daily

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Bleeding times
Clinical Impact:	Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention:	This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact:	The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention:	Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact:	Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention:	This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.

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AED Co - administered	AED Concentration	Topiramate Concentration
Phenytoin	NCor25%increase ^a	48%decrease
Carbamazepine(CBZ)	NC	40%decrease
CBZepoxide ^b	NC	NE
Valproic acid	11%decrease	14%decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NCatTPM dosesupto400 mg/day	13%decrease

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Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of aripiprazole with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.8)].
Benzodiazepines (e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.8)]	Monitor sedation and blood pressure. Adjust dose accordingly.

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Table 11: Effect of Other Drugs on Voriconazole Pharmacokinetics
Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (C_max and AUC_τ after 200 mg Q12h)	Recommendations for Voriconazole Dosage Adjustment/Comments
RifampinResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg Q12h voriconazole to healthy subjects, and Rifabutin (CYP450 Induction)	Significantly Reduced	Contraindicated
EfavirenzResults based on in vivo clinical study following repeat oral dosing with 400 mg Q12h for 1 day, then 200 mg Q12h for at least 2 days voriconazole to healthy subjects (CYP450 Induction)	Significantly Reduced	When voriconazole is coadministered with efavirenz, voriconazole maintenance dose should be increased to 400 mg Q12h and efavirenz should be decreased to 300 mg Q24h (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION-Dosage Adjustment)
High-dose Ritonavir (400mg Q12h) (CYP450 Induction)	Significantly Reduced	Contraindicated
Low-dose Ritonavir (100mg Q12h) (CYP450 Induction)	Reduced	Coadministration of voriconazole and low-dose ritonavir (100 mg Q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Phenytoin (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV every 12 hrs or from 200 mg to 400 mg orally every 12 hrs (100 mg to 200 mg orally every 12 hrs in patients weighing less than 40 kg)
St. John's Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to voriconazole
	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Careful assessment of voriconazole effectiveness

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edema	hypothyroidism
hereditary coumarin resistance	nephrotic syndrome
hyperlipemia


Interacting Drug	Interaction
Multivalent cation-containing products including : antacids, sucralfate, multivitamins
Warfarin
Class IA and Class III antiarrhythmics:
Antidiabetic agents

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Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.

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Table 2: Drug-Thyroidal Axis Interactions
	Drug or Drug Class		Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
		Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
		Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
		Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
		Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
		Amiodarone Iodide (including iodine- containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
	Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
	Drugs that may increase		Drugs that may decrease
	serum TBG concentration		serum TBG concentration
	Clofibrate		Androgens / Anabolic Steroids
	Estrogen-containing oral		Asparaginase
	contraceptives		Glucocorticoids
	Estrogens (oral)		Slow-Release Nicotinic Acid
	Heroin / Methadone
	5-Fluorouracil
	Mitotane
	Tamoxifen
	Drugs that may cause protein-binding site displacement
	Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)		Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
	Carbamazepine Hydantoins Phenobarbital Rifampin		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
	Drugs that may decrease T ₄ 5' - deiodinase activity
	Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)		Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, Ieading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
	Miscellaneous
	Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives		Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
	Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
	Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin		Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
	Cardiac Glycosides		Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
	Cytokines - Interferon-α - Interleukin-2		Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
	Growth Hormones - Somatrem - Somatropin		Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
	Ketamine		Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
	Methylxanthine Bronchodilators - (e.g., Theophylline)		Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
	Radiographic Agents		Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
	Sympathomimetics		Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
	Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics		These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.5, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine, danazol	Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
↓= Decreased (induces lamotrigine gluronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
?= Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine and carbamazepine epoxide	? carbamazepine epoxide	May increase carbamazepine epoxide levels.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 7 Summary of AED Interactions with Trileptal
AED Coadministered	Dose of AED (mg/day)	Trileptal Dose (mg/day)	Influence of Trileptal on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400-2000	900	nc ¹	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100-150	600-1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250-500	600-1800 >1200-2400	nc ^1,2 up to 40% increase ³ [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400-2800	600-1800	nc ¹	18% decrease [CI: 13% decrease, 40% decrease]

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Antibiotics	Antineoplastic	Antifungals	Anti- Inflammatory Drugs	Gastrointestinal Agents	Immunosuppressives	Other Drugs
ciprofloxacingentamicin tobramycin trimethoprim with sulfamethoxazole vancomycin	melphalan	amphotericin Bketoconazole	azapropazoncolchicine diclofenacnaproxen sulindac	cimetidine ranitidine	tacrolimus	fibric acid derivatives (e.g., bezafibrate, fenofibrate)

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistatcontaining products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin dailyFor patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion–the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide(including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide(including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄, and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5’-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.

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Table 18. Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9- Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Co-administered Drug	Dosing Schedule		Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference)		Risperidone Dose Recommendation
	Co-administered Drug	Risperidone	AUC	C_max
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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a = Plasma concenrtration increased 25% in some patients, generally those on a twice a day dosing regimen
of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Table 3Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( 7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( 7)
Phenytoin	Monitor phenytoin level ( 7)
Methotrexate	Monitor for methotrexate toxicity ( 7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine ( 7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin tablets absorption. Take 2 hours before or 6 hours after ciprofloxacin tablets ( 7)

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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AED Co - administered	AED Concentration	Topiramate Concentration
Phenytoin	NCor25%increase ^a	48%decrease
Carbamazepine(CBZ)	NC	40%decrease
CBZepoxide ^b	NC	NE
Valproic acid	11%decrease	14%decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NCatTPM dosesupto400 mg/day	13%decrease

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Table 18. Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9- Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Co-administered Drug	Dosing Schedule		Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference)		Risperidone Dose Recommendation
	Co-administered Drug	Risperidone	AUC	C_max
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Table 13. Established and Other Potentially Significant Drug Interactions
↓= Decreased (induces lamotrigine glucuronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
?= Conflicting data.
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide Is not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)	VIAGRA 100 mg
Supine	7.9 (4.6, 11.1)
Standing	4.3 (-1.8,10.3)

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin	Monitor phenytoin level (7)
Methotrexate	Monitor for methotrexate toxicity (7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)

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Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs that Interfere with Hemostasis
Clinical Impact:	Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention:	Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, or Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention:	During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology (12.3)].
Intervention:	During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention:	The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
albuterol, systemic and inhaled	felodipinefinasteride	nizatidinenorfloxacin
amoxicillin	hydrocortisone	ofloxacin
ampicillin, with or without sulbactam	isoflurane isoniazid	omeprazole prednisone, prednisolone
atenolol	isradipine	ranitidine
azithromycin	influenze vaccine	rifabutin
caffeine, dietary ingestion	ketoconazo lelomefloxacin	Roxithromycin sorbitol (purgative doses do onot inhibit theophylline absorption)
cefaclor	mebendazole
co-trimoxazole (trimethoprim and sulfamethoxazole)	medroxyprogesteronemethylprednisolone	sucralfate
diltiazem	metronidazole	terbutaline, systemic
dirithromycin	metoprolol	terfenadine
enflurane	nadolol	tetracycline
famotidine	nifedipine	tocainide

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Table 5: Summary of Effect of Coadministered Drugs on Exposure to Asenapine in Healthy Volunteers
Coadministered drug (Postulated effect on CYP450/UGT)	Dose schedules		Effect on asenapine pharmacokinetics		Recommendation
Coadministered drug (Postulated effect on CYP450/UGT)	Coadministered drug	Asenapine	C_max	AUC_0-∞
Fluvoxamine (CYP1A2 inhibitor)	25 mg twice daily for 8 days	5-mg Single Dose	+13%	+29%	Coadminister with cautionThe full therapeutic dose of fluvoxamine would be expected to cause a greater increase in asenapine plasma concentrations. AUC: Area under the curve.
Paroxetine (CYP2D6 inhibitor)	20 mg once daily for 9 days	5-mg Single Dose	–13%	–9%	No SAPHRIS dose adjustment required [see Drug Interactions (7.2)]
Imipramine (CYP1A2/2C19/3A4 inhibitor)	75-mg Single Dose	5-mg Single Dose	+17%	+10%	No SAPHRIS dose adjustment required
Cimetidine (CYP3A4/2D6/1A2 inhibitor)	800 mg twice daily for 8 days	5-mg Single Dose	–13%	+1%	No SAPHRIS dose adjustment required
Carbamazepine (CYP3A4 inducer)	400 mg twice daily for 15 days	5-mg Single Dose	–16%	–16%	No SAPHRIS dose adjustment required
Valproate (UGT1A4 inhibitor)	500 mg twice daily for 9 days	5-mg Single Dose	2%	–1%	No SAPHRIS dose adjustment required

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CYP2C19 or CYP3A4 Inducers
Clinical Impact:	Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention:	St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions (5.9)]. Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:	Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
Intervention:	Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole.

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Table II Clinically significant drug interactions with theophylline*.
* Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
** Average effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Drug	Type of Interaction	Effect**
Adenosine	Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.
Alcohol	A single large dose of alcohol (3 ml/kg of whiskey) decreases theophylline clearance for up to 24 hours.	30% increase
Allopurinol	Decreases theophylline clearance at allopurinol doses ≥600 mg/day.	25% increase
Aminoglutethimide	Increase theophylline clearance by induction of microsomal enzyme activity.	25% decrease
Carbamazepine	Similar to aminoglutethimide.	30% decrease
Cimetidine	Decreases theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase
Ciprofloxacin	Similar to cimetidine.	40% increase
Clarithromycin	Similar to erythromycin.	25% increase
Diazepam	Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant while, theophylline blocks adenosine receptors	Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram	Decreases theophylline clearance by inhibiting hydroxylation and demethylation	50% increase
Enoxacin	Similar to cimetidine.	300% increase
Ephedrine	Synergistic CNS effects of nausea, nervousness, and insomnia.	Increased frequency of nausea, nervousness, and insomnia
Erythromycin	Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen	Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.	30% increase
Flurazepam	Similar to diazepam.	Similar to diazepam.
Fluvoxamine	Similar to cimetidine	Similar to cimetidine
Halothane	Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.	Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A	Decreases theophylline clearance.	100% increase
Isoproterenol (IV)	Increases theophylline clearance.	20% decrease
Ketamine	Pharmacologic	May lower theophylline seizure threshold.
Lithium	Theophylline increases renal lithium clearance.	Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam	Similar to diazepam.	Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.	20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine.	Similar to disulfiram.	80% increase
Midazolam	Similar to diazepam.	Similar to diazepam.
Moricizine	Increases theophylline clearance.	25% decrease
Pancuronium	Theophylline may antagonize nondepolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.	Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline	Decreases theophylline clearance.	30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.	25% decrease after two weeks of concurrent PB.
Phenytoin	Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.	Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone	Decreases theophylline clearance and pharmacologic interaction.	40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and pharmacologic interaction	100% increase Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin	Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.	20-40% decrease
Sulfinpyrazone	Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.	20% decrease
Tacrine	Similar to cimetidine, also increase renal clearance of theophylline.	90% increase
Thiabendazole	Decreases theophylline clearance.	190% increase
Ticlopidine	Decreases theophylline clearance.	60% increase
Troleandomycin	Similar to erythromycin.	33-100% increase depending on troleandomycin dose.
Verapamil	Similar to disulfiram.	20% increase

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Drugs that Affect Renal Function	A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDs], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics	Dofetilide	Concomitant administration with digoxin was associated with a higher rate of torsades de pointes.
	Sotalol	Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
	Dronedarone	Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog	Teriparatide	Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement	Thyroid	Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics	Epinephrine Norepinephrine Dopamine	Can increase the risk of cardiac arrhythmias.
Neuromuscular Blocking Agents	Succinylcholine	May cause sudden extrusion of potassium from muscle cells, causing arrhythmias in patients taking digoxin.
Supplements	Calcium	If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers		Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.

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DRUG	DESCRIPTION OF INTERACTION
Heparin	Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparintreated patients.
Pyrazinamide	Inhibits pyrazinamide induced hyperuricemia.
Uricosuric Agents	Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.

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Summary of AED interactions with topiramate ( 7.1).
AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase ^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide ^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400mg/day	13% decrease

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Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.6).]
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported . Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [see Adverse Reactions (6.1).]
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution 2-fold increase in exposure	Monitor for sildenafil toxicity (see Pharmacokinetics -(12.3)-] .
Duloxetine	Avoid Use 5-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx ^® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2)].	Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

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Table 9. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug Name	Effect on Concentration of Lopinavir or Concomitant Drug	Clinical Comments
HIV-1 Antiviral Agents
HIV-1 Protease Inhibitor: fosamprenavir/ritonavir	↓ amprenavir ↓ lopinavir	An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: indinavir*	↑ indinavir	Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily [see Clinical Pharmacology (12.3)]. KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor: nelfinavir*	↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir	KALETRA should not be administered once daily in combination with nelfinavir [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
HIV-1 Protease Inhibitor: ritonavir*	↑ lopinavir	Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: saquinavir*	↑ saquinavir	The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor: tipranavir	↓ lopinavir AUC and C_min	KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily).
HIV CCR5 – Antagonist: maraviroc	↑ maraviroc	Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry^® (maraviroc).
Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz, nevirapine	↓ lopinavir	KALETRA dose increase is recommended in all patients [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)]. Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz. Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz. KALETRA should not be administered once daily in combination with efavirenz or nevirapine [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine	↑ lopinavir	Appropriate doses of the combination with respect to safety and efficacy have not been established.
Nucleoside Reverse Transcriptase Inhibitor: didanosine		KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).
Nucleoside Reverse Transcriptase Inhibitor: tenofovir	↑ tenofovir	KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitors: abacavir zidovudine	↓ abacavir ↓ zidovudine	KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.
Other Agents
Antiarrhythmics e.g.: amiodarone, bepridil, lidocaine (systemic), quinidine	↑ antiarrhythmics	Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.
Anticancer Agents: vincristine, vinblastine, dasatinib, nilotinib	↑ anticancer agents	Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents. For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.
Anticoagulants: warfarin, rivaroxaban	↑ rivaroxaban	Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored. Avoid concomitant use of rivaroxaban and KALETRA. Co-administration of KALETRA and rivaroxaban is expected to result in increased exposure of rivaroxaban which may lead to risk of increased bleeding.
Anticonvulsants: carbamazepine, phenobarbital, phenytoin	↓ lopinavir ↓ phenytoin	KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
Anticonvulsants: lamotrigine, valproate	↓ lamotrigine ↓ or ↔ valproate	Co-administration of KALETRA and lamotrigine or valproate may decrease the exposure of lamotrigine or valproate. A dose increase of lamotrigine or valproate may be needed when co-administered with KALETRA and therapeutic concentration monitoring for lamotrigine may be indicated; particularly during dosage adjustments [see Clinical Pharmacology (12.3)].
Antidepressant: bupropion	↓ bupropion ↓ active metabolite, hydroxybupropion	Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant: trazodone	↑ trazodone	Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-infective: clarithromycin	↑ clarithromycin	For patients with renal impairment, the following dosage adjustments should be considered: • For patients with CL_CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. • For patients with CL_CR < 30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary.
Antifungals: ketoconazole*, itraconazole, voriconazole	↑ ketoconazole ↑ itraconazole ↓ voriconazole	High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended. Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients.
Anti-gout: colchicine	↑ colchicine	Patients with renal or hepatic impairment should not be given colchicine with KALETRA. Treatment of gout flares-co-administration of colchicine in patients on KALETRA: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on KALETRA: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial: rifabutin*	↑ rifabutin and rifabutin metabolite	Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antimycobacterial: rifampin	↓ lopinavir	May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone [see Clinical Pharmacology (12.3) for magnitude of interaction].
Antiparasitic: atovaquone	↓ atovaquone	Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Benzodiazepines: parenterally administered midazolam	↑ midazolam	Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam [see Contraindications (4)]. If KALETRA is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Contraceptive: ethinyl estradiol*	↓ ethinyl estradiol	Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.
Corticosteroids (systemic): e.g. budesonide, dexamethasone, prednisone	↓ lopinavir ↑ glucocorticoids	Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly. Concomitant use may result in increased steroid concentrations and reduced serum cortisol concentrations. Concomitant use of glucocorticoids that are metabolized by CYP3A, particularly for long-term use, should consider the potential benefit of treatment versus the risk of systemic corticosteroid effects. Concomitant use may increase the risk for development of systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression.
Dihydropyridine Calcium Channel Blockers: e.g. felodipine, nifedipine, nicardipine	↑ dihydropyridine calcium channel blockers	Caution is warranted and clinical monitoring of patients is recommended.
Disulfiram/metronidazole		KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Endothelin Receptor Antagonists: bosentan	↑ bosentan	Co-administration of bosentan in patients on KALETRA: In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Co-administration of KALETRA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA. After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HCV-Protease Inhibitor: boceprevir	↓ lopinavir ↓ boceprevir ↓ ritonavir	It is not recommended to co-administer KALETRA and boceprevir. Concomitant administration of KALETRA and boceprevir reduced boceprevir, lopinavir and ritonavir steady-state exposures [see Clinical Pharmacology (12.3)].
HCV-Protease Inhibitor: telaprevir	↓ telaprevir ↔ lopinavir	It is not recommended to co-administer KALETRA and telaprevir. Concomitant administration of KALETRA and telaprevir reduced steady-state telaprevir exposure, while the steady-state lopinavir exposure was not affected [see Clinical Pharmacology (12.3)].
HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin	↑ atorvastatin ↑ rosuvastatin	Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day. See Drugs with No Observed or Predicted Interactions with KALETRA (7.4) and Clinical Pharmacology (12.3) for drug interaction data with other HMG-CoA reductase inhibitors.
Immunosuppressants: e.g. cyclosporine, tacrolimus, sirolimus	↑ immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Inhaled or Intranasal Steroids e.g.: fluticasone, budesonide	↑ glucocorticoids	Concomitant use of KALETRA and fluticasone or other glucocorticoids that are metabolized by CYP3A is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. Concomitant use may result in increased steroid concentrations and reduce serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during postmarketing use in patients when certain ritonavir-containing products have been co-administered with fluticasone propionate or budesonide.
Long-acting beta-adrenoceptor Agonist: salmeterol	↑ salmeterol	Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesics: methadone,* fentanyl	↓ methadone ↑ fentanyl	Dosage of methadone may need to be increased when co-administered with KALETRA. Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA.
PDE5 inhibitors: avanafil, sildenafil, tadalafil, vardenafil	↑ avanafil ↑ sildenafil ↑ tadalafil ↑ vardenafil	Do not use KALETRA with avanafil because a safe and effective avanafil dosage regimen has not been established. Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio^®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA [see Contraindications (4)]. The following dose adjustments are recommended for use of tadalafil (Adcirca^®) with KALETRA: Co-administration of ADCIRCA in patients on KALETRA: In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Co-administration of KALETRA in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: It is recommended not to exceed the following doses: • Sildenafil: 25 mg every 48 hours • Tadalafil: 10 mg every 72 hours • Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events.
* see Clinical Pharmacology (12.3) for magnitude of interaction.

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin	Monitor phenytoin level (7)
Methotrexate	Monitor for methotrexate toxicity (7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)

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Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 6. Drugs That Should Not Be Coadministered With RESCRIPTOR
Drug Class: Drug Name	Clinical Comment
Anticonvulsant agents: Phenytoin, phenobarbital, carbamazepine	May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of NNRTIs.
Antihistamines: Astemizole, terfenadine	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Antimycobacterials: Rifabutin,^a rifampin^a	May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of NNRTIs or other coadministered antiviral agents.
Ergot Derivatives: Dihydroergotamine, ergonovine, ergotamine, methylergonovine	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
GI motility agent: Cisapride	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Herbal Products: St. John’s wort (Hypericum perforatum)	May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of NNRTIs.
HMG-CoA reductase inhibitors: Lovastatin, simvastatin	Potential for serious reactions such as risk of myopathy including rhabdomyolysis.
Neuroleptic: Pimozide	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Sedative/hypnotics: Alprazolam, midazolam, triazolam	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine	Do not exceed 10 mg atorvastatin daily
Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir)	Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used.

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Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (C_max and AUC _τ after 200 mg q12h)	Recommendations for Voriconazole Dosage Adjustment/Comments
Rifampin* and Rifabutin* (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (400 mg q24h) (CYP450 Induction) Efavirenz (300 mg q24h) (CYP450 Induction)	Significantly Reduced Slight Decrease in AUC_τ	Contraindicated When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h) (CYP450 Induction) Low-dose Ritonavir (100 mg q12h) (CYP450 Induction)	Significantly Reduced Reduced	Contraindicated Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Phenytoin* (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John’s Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives** containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole** (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIs*** (CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure) A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to voriconazole Careful assessment of voriconazole effectiveness

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Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.8)].

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Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
*Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	C _m _a _x
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing.
	20 mg/day	4 mg/day	1.6	-	Do not exceed 8 mg/day
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers)
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin	Monitor phenytoin level (7)
Methotrexate	Monitor for methotrexate toxicity (7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline. Refer to PRECAUTIONS , Drug Interactions for information regarding table.
albuterol,	lomefloxacin
systemic and inhaled	mebendazole
amoxicillin	medroxyprogesterone
ampicillin,	methylprednisolone
with or without sulbactam	metronidazole
atenolol	metoprolol
azithromycin	nadolol
caffeine,	nifedipine
dietary ingestion	nizatidine
cefaclor	norfloxacin
co-trimoxazole	ofloxacin
(trimethoprim and	omeprazole
sulfamethoxazole)	prednisone, prednisolone
diltiazem	ranitidine
dirithromycin	rifabutin
enflurane	roxithromycin
famotidine	sorbitol
felodipine	(purgative doses do not
finasteride	inhibit theophylline
hydrocortisone	absorption)
isoflurane	sucralfate
isoniazid	terbutaline, systemic
isradipine	terfenadine
influenza vaccine	tetracycline
ketoconazole	tocainide

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Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of naproxen and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of naproxen and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
* For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily*
Grapefruit juice	Avoid grapefruit juice

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistatcontaining products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin dailyFor patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
*Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	C _m _a _x
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing.
	20 mg/day	4 mg/day	1.6	-	Do not exceed 8 mg/day
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers)
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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NA – Not available/reported
Digoxin concentrations increased greater than 50%
	Digoxin Serum Concentration Increase	Digoxin AUC Increase	Recommendations
Amiodarone	70%	NA	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
Captopril	58%	39%
Clarithromycin	NA	70%
Dronedarone	NA	150%
Gentamicin	129-212%	NA
Erythromycin	100%	NA
Itraconazole	80%	NA
Nitrendipine	57%	15%
Propafenone	NA	60-270%
Quinidine	100%	NA
Ranolazine	50%	NA
Ritonavir	NA	86%
Tetracycline	100%	NA
Verapamil	50-75%	NA
Digoxin concentrations increased less than 50%
Atorvastatin	22%	15%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
Carvedilol	16%	14%
Diltiazem	20%	NA
Indomethacin	40%	NA
Nefazodone	27%	15%
Nifedipine	45%	NA
Propantheline	24%	24%
Quinine	NA	33%
Saquinavir	27%	49%
Spironolactone	25%	NA
Telmisartan	20-49%	NA
Tolvaptan	30%	NA
Trimethoprim	22-28%	NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole, rabeprazole,			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate, sulfasalazine			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20-40% as necessary.
No significant Digoxin exposure changes
Please refer to section 12 for a complete list of drugs which were studied but reported no significant changes on digoxin exposure.			No additional actions are required.

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Interacting Drug	Interaction
Antacids, sucralfate, multivitamins, and other products containing multivalent cations	Moxifloxacin absorption is decreased. Administer moxifloxacin hydrochloride tablet at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3, 17)
Warfarin	Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. (6.4, 7.2, 12.3)
Class IA and Class III antiarrhythmics:	Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.3, 7.5)
Antidiabetic agents	Carefully monitor blood glucose (5.10, 7.3)

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir )	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)	Do not exceed 40 mg atorvastatin daily

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Table 2: Drug — Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion -the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥100 mg/day or equivalent); Octreotide (>100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport — but FT₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone > 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.

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Table 2: Clinically Significant Drug Interactions with Diclofenac
Drugs That Interfere with Hemostasis
Clinical Impact	● Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. ● Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention	Monitor patients with concomitant use of diclofenac sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see WARNINGS AND PRECAUTIONS (5.11)]
Aspirin
Clinical Impact :	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of NSAID alone [see WARNINGS AND PRECAUTIONS (5.2)]
Intervention	Concomitant use of diclofenac sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see WARNINGS AND PRECAUTIONS (5.11)]. Diclofenac sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE inhibitors , Angiotensin Receptor Blockers , and Beta - Blockers
Clinical Impact :	● NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). ● In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention :	● During concomitant use of diclofenac sodium and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained ● During concomitant use of diclofenac sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see WARNINGS AND PRECAUTIONS(5.6)] ● When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact :	Clinical studies, as well as post-marketing observations, showed that NSAIDS reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention :	During concomitant use of diclofenac sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see WARNINGS AND PRECAUTIONS (5.6)].
Digoxin
Clinical Impact:	The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life digoxin.
Intervention :	During concomitant use of diclofenac sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact :	NSAIDS have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention :	During concomitant use of diclofenac sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact ;	Concomitant use of NSAIDs and methotrexate may increase the risk of methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of diclofenac sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact :	Concomitant use of diclofenac sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention :	During concomitant use of diclofenac sodium and cyclosporine, monitor patients for signs or worsening renal function.
NSAIDs and Salicylates
Clinical Impact :	Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see WARNINGS AND PRECAUTIONS (5.2)]. Concomitant use of oral NSAIDs with diclofenac sodium has been evaluated in one Phase 3 controlled trial and in combination with oral diclofenac, compared to oral diclofenac alone, resulted in a higher rate of rectal hemorrhage (3% vs. less than 1%), and more frequent abnormal creatinine (12% vs. 7%), urea (20% vs. 12%) and hemoglobin (13% vs. 9%).
Intervention :	The concomitant use of diclofenac with other NSAIDs or salicyclates is not recommended. Do not use combination therapy with diclofenac sodium and an oral NSAID unless the benefit outweighs the risk and conduct periodic laboratory evaluations
Pemetrexed
Clinical Impact :	Concomitant use of diclofenac sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention :	During concomitant use of diclofenac sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.

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AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxideIs not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio Change relative to reference )		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	C_max	Risperidone Dose Recommendation
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

Table name:

Digoxin concentrations increased > 50%
	Digoxin Serum Concentration Increase	Digoxin AUC Increase	Recommendations
Amiodarone	70%	NA	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin dose by approximately 30% to 50% and continue monitoring.
Captopril	58%	39%
Nitrendipine	57%	15%
Propafenone	35-85%	NA
Quinidine	100%	NA
Ranolazine	87%	88%
Ritonavir	NA	86%
Verapamil	50-75%	NA
Digoxin concentrations increased < 50%
Carvedilol	16%	14%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin dose by approximately 15% to 30% and continue monitoring.
Diltiazem	20%	NA
Nifedipine	45%	NA
Rabeprazole	29%	19%
Telmisartan	20%	NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, Azithromycin, Clarithromycin, Cyclosporine, Diclofenac, Diphenoxylate, Epoprostenol, Erythromycin, Esomeprazole, Indomethacin, Itraconazole, Ketoconazole, Lansoprazole, Metformin, Omeprazole, Propantheline, Spironolactone, Tetracycline			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, Activated Charcoal, Albuterol, Antacids, Anti-cancer drugs, Cholestyramine, Colestipol, Exenatide, Kaolin-pectin, Meals High in Bran, Metoclpramide, Miglitol, Neomycin, Rifampin, Salbutamol, St. John’s Wort, Sucralfate, Sulfasalazine			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20% to 40% as necessary.
No significant Digoxin concentrations changes
Please refer to section 12.3 for a complete list of drugs which were studied but reported no significant changes on digoxin exposure.			No additional actions are required.

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Table 4. Effects of Other Drugs/Substances on ENVARSUS XR^a
^a ENVARSUS XR dosage adjustment recommendation based on observed effect of coadministered drug on tacrolimus exposures [see Clinical Pharmacology (12.2) ], literature reports of altered tacrolimus exposures, or the other drug’s known CYP3A inhibitor/inducer status ^b High dose or double strength grapefruit juice is a strong CYP3A inhibitor; low dose or single strength grapefruit juice is a moderate CYP3A inhibitor ^c Strong CYP3A inhibitor/inducer, based on reported effect on exposures to tacrolimus along with supporting in vitro CYP3A inhibitor/inducer data, or based on drug-drug interaction studies with midazolam (sensitive CYP3A probe substrate)
Drug/Substance Class or Name	Drug Interaction Effect	Recommendations
Grapefruit or grapefruit juice^b	May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.6, 5.10) ]	Avoid grapefruit or grapefruit juice
Alcohol	May modify the rate of tacrolimus release	Avoid alcoholic beverages
Strong CYP3A Inducers^c such as: Antimycobacterials (e.g., rifampin, rifabutin), anticonvulsants (e.g., phenytoin, carbamazepine and phenobarbital), St John’s Wort	May decrease tacrolimus whole blood trough concentrations and increase the risk of rejection [see Warnings and Precautions (5.9) ]	Increase ENVARSUS XR dose and monitor tacrolimus whole blood trough concentrations [see Dosage and Administration (2.3) and Clinical Pharmacology (12.2) ]
Strong CYP3A Inhibitors^c, such as: Protease inhibitors (e.g., nelfinavir, telaprevir, boceprevir, ritonavir), azole antifungals (e.g., voriconazole, posaconazole, itraconazole, ketoconazole), antibiotics (e.g., clarithromycin, troleandomycin, chloramphenicol), nefazodone	May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.6, 5.9, 5.10) ]	Reduce ENVARSUS XR dose (for voriconazole and posaconazole, give one-third of the original dose) and adjust dose based on tacrolimus whole blood trough concentrations [see Dosage and Administration (2.3) and Clinical Pharmacology (12.2) ]
Mild or Moderate CYP3A Inhibitors, such as: antibiotics (e.g., erythromycin), calcium channel blockers (e.g., verapamil, diltiazem, nifedipine, nicardipine), amiodarone, danazol, ethinyl estradiol, cimetidine, lansoprazole and omeprazole, azole antifungals (e.g., clotrimazole, fluconazole)	May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.6, 5.10) ]	Monitor tacrolimus whole blood trough concentrations and reduce ENVARSUS XR dose if needed [see Dosage and Administration (2.3) and Clinical Pharmacology (12.2) ]
Other drugs, such as: Magnesium and aluminum hydroxide antacids Metoclopramide	May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.6, 5.10) ]	Monitor tacrolimus whole blood trough concentrations and reduce ENVARSUS XR dose if needed [see Dosage and Administration (2.3) and Clinical Pharmacology (12.2) ]
Mild or Moderate CYP3A Inducers, such as: Methylprednisolone, prednisone	May decrease tacrolimus concentrations	Monitor tacrolimus whole blood trough concentrations and adjust ENVARSUS XR dose if needed [see Dosage and Administration (2.3) ]

Table name:

Interacting Drug	Interaction
Warfarin	Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. (6.4, 7.1, 12.3)
Class IA and Class III antiarrhythmics:	Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.6, 7.4)
Antidiabetic agents	Carefully monitor blood glucose. (5.12, 7.2)

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of this product. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.12, 7.3)

Table name:

Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Calcium Channel Blockers	Antifungals	Antibiotics	Glucocorticoids	Other Drugs
diltiazem	fluconazole	azithromycin	methylprednisolone	allopurinol
nicardipine	itraconazole	clarithromycin		amiodarone
verapamil	ketoconazole	erythromycin		bromocriptine
	voriconazole	quinupristin/ dalfopristin		colchicine
				danazol
				imatinib
				metoclopramide
				nefazodone
				oral contraceptives

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Digoxin Concentrations Increased Greater than 50%
	Digoxin Serum Concentration Increase	Digoxin AUC Increase	Recommendations
Amiodarone	70%	NA	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin dose by approximately 30% to 50% or by modifying the dosing frequency and continue monitoring.
Captopril	58%	39%
Clarithromycin	NA	70%
Dronedarone	NA	150%
Gentamicin	129 to 212%	NA
Erythromycin	100%	NA
Itraconazole	80%	NA
Lapatinib	NA	180%
Propafenone	NA	60 to 270%
Quinidine	100%	NA
Ranolazine	50%	NA
Ritonavir	NA	86%
Telaprevir	50%	85%
Tetracycline	100%	NA
Verapamil	50 to 75%	NA
Digoxin Concentrations Increased Less than 50%
Atorvastatin	22%	15%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin dose by approximately 15% to 30% or by modifying the dosing frequency and continue monitoring.
Carvedilol	16%	14%
Conivaptan	33%	43%
Diltiazem	20%	NA
Indomethacin	40%	NA
Nefazodone	27%	15%
Nifedipine	45%	NA
Propantheline	24%	24%
Quinine	NA	33%
Rabeprazole	29%	19%
Saquinavir	27%	49%
Spironolactone	25%	NA
Telmisartan	20 to 49%	NA
Ticagrelor	31%	28%
Tolvaptan	30%	20%
Trimethoprim	22 to 28%	NA
Digoxin Concentrations Increased, but Magnitude is Unclear
Alprazolam, Azithromycin, Cyclosporine, Diclofenac, Diphenoxylate, Epoprostenol, Esomeprazole, Ibuprofen, Ketoconazole, Lansoprazole, Metformin, Omeprazole			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin Concentrations Decreased
Acarbose, Activated Charcoal, Albuterol, Antacids, certain cancer chemotherapy or radiation therapy, Cholestyramine, Colestipol, Exenatide, Kaolin-pectin, Meals High in Bran, Metoclopramide, Miglitol, Neomycin, Penicillamine, Phenytoin, Rifampin, St. John’s Wort, Sucralfate, Sulfasalazine			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20% to 40% as necessary.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

Table name:

AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease
^a= Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. ^b = Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. NE = Not Evaluated

Table name:

AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

Table name:

AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxideIs not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease
NC = Less than 10% change in plasma concentration. NE = Not Evaluated.

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Table 8: Clinically Significant Drug Interactions with Clarithromycin
Drugs That Are Affected By Clarithromycin
Drug(s) with Pharmacokinetics Affected by Clarithromycin		Recommendation	Comments
Antiarrhythmics: Disopyramide Quinidine Dofetilide Amiodarone Sotalol Procainamide Digoxin		Not Recommended Use With Caution	Disopyramide, Quinidine: There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs [see Warnings and Precautions (5.3)]. Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine. There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide. Digoxin: Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are co-administered, inhibition of Pgp by clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range.
Oral Anticoagulants: Warfarin		Use With Caution	Oral anticoagulants: Spontaneous reports in the postmarketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously [see Warnings and Precautions (5.4)].
Antiepileptics: Carbamazepine		Use With Caution	Carbamazepine: Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered. Increased serum concentrations of carbamazepine were observed in clinical trials with clarithromycin. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with carbamazepine.
Antifungals: Itraconazole Fluconazole		Use With Caution No Dose Adjustment	Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly (see also Itraconazole under “Drugs That Affect Clarithromycin” in the table below). Clarithromycin may increase the plasma concentrations of itraconazole. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions. Fluconazole: [see Pharmacokinetics (12.3)]
Anti-Gout Agents: Colchicine (in patients with renal or hepatic impairment) Colchicine (in patients with normal renal and hepatic function)		Contraindicated Use With Caution	Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. The dose of colchicine should be reduced when co-administered with clarithromycin in patients with normal renal and hepatic function [see Contraindications (4.4) and Warnings and Precautions (5.4)].
Antipsychotics: Pimozide Quetiapine		Contraindicated	Pimozide: [See Contraindications (4.2)] Quetiapine: Quetiapine is a substrate for CYP3A4, which is inhibited by clarithromycin. Co-administration with clarithromycin could result in increased quetiapine exposure and possible quetiapine related toxicities. There have been postmarketing reports of somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation during concomitant administration. Refer to quetiapine prescribing information for recommendations on dose reduction if co-administered with CYP3A4 inhibitors such as clarithromycin.
Antispasmodics: Tolterodine (patients deficient in CYP2D6 activity)		Use With Caution	Tolterodine: The primary route of metabolism for tolterodine is via. CYP2D6. However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via. CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when co-administered with clarithromycin.
Antivirals: Atazanavir Saquinavir (in patients with decreased renal function) Ritonavir Etravirine Maraviroc Boceprevir (in patients with normal renal function) Didanosine Zidovudine		Use With Caution No Dose Adjustment	Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)]. Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction (see Saquinavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)]. Ritonavir, Etravirine: (see Ritonavir and Etravirine under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)]. Maraviroc: Clarithromycin may result in increases in maraviroc exposures by inhibition of CYP3A metabolism. See Selzentry^® prescribing information for dose recommendation when given with strong CYP3A inhibitors such as clarithromycin. Boceprevir: Both clarithromycin and boceprevir are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when co-administered. No dose adjustments are necessary for patients with normal renal function (see Victrelis^® prescribing information). Zidovudine: Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Administration of clarithromycin and zidovudine should be separated by at least two hours [see Pharmacokinetics (12.3)].
Calcium Channel Blockers: Verapamil Amlodipine Diltiazem Nifedipine		Use With Caution	Verapamil: Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, [see Warnings and Precautions (5.4)]. Amlodipine, Diltiazem: [See Warnings and Precautions (5.4)] Nifedipine: Nifedipine is a substrate for CYP3A. Clarithromycin and other macrolides are known to inhibit CYP3A. There is potential of CYP3A-mediated interaction between nifedipine and clarithromycin. Hypotension and peripheral edema were observed when clarithromycin was taken concomitantly with nifedipine [see Warnings and Precautions (5.4)].
Ergot Alkaloids: Ergotamine Dihydroergotamine		Contraindicated	Ergotamine, Dihydroergotamine: Postmarketing reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4.6)].
Gastroprokinetic Agents: Cisapride		Contraindicated	Cisapride: [See Contraindications (4.2)]
HMG-CoA Reductase Inhibitors: Lovastatin Simvastatin Atorvastatin Pravastatin Fluvastatin		Contraindicated Use With Caution No Dose Adjustment	Lovastatin, Simvastatin, Atorvastatin, Pravastatin, Fluvastatin: [See Contraindications (4.5) and Warnings and Precautions (5.4)]
Hypoglycemic Agents: Nateglinide Pioglitazone Repaglinide Rosiglitazone Insulin		Use With Caution	Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)] Insulin: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]
Immunosuppressants: Cyclosporine Tacrolimus		Use With Caution	Cyclosporine: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine. Tacrolimus: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with tacrolimus.
Phosphodiesterase inhibitors: Sildenafil Tadalafil Vardenafil		Use With Caution	Sildenafil, Tadalafil, Vardenafil: Each of these phosphodiesterase inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant administration of clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil, or vardenafil will result in increased exposure of these phosphodiesterase inhibitors. Co-administration of these phosphodiesterase inhibitors with clarithromycin is not recommended. Increased systemic exposure of these drugs may occur with clarithromycin; reduction of dosage for phosphodiesterase inhibitors should be considered (see their respective prescribing information).
Proton Pump Inhibitors: Omeprazole		No Dose Adjustment	Omeprazole: The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when coadministered with clarithromycin as a result of increased omeprazole exposures [see Pharmacokinetics (12.3)] (see also Omeprazole under “Drugs That Affect Clarithromycin” in the table below).
Xanthine Derivatives: Theophylline		Use With Caution	Theophylline: Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations [see Pharmacokinetics (12.3)]. Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range.
Triazolobenzodiazepines and Other Related Benzodiazepines: Midazolam Alprazolam Triazolam Temazepam Nitrazepam Lorazepam		Use With Caution No Dose Adjustment	Midazolam: When oral midazolam is co-administered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated [see Warnings and Precautions (5.4) and Pharmacokinetics (12.3)]. Triazolam, Alprazolam: Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is co-administered with clarithromycin. There have been postmarketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested. In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines. Temazepam, Nitrazepam, Lorazepam: For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.
Cytochrome P450 Inducers: Rifabutin		Use With Caution	Rifabutin: Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis (see Rifabutin under “Drugs That Affect Clarithromycin” in the table below).
Other Drugs Metabolized by CYP3A: Alfentanil Bromocriptine Cilostazol Methylprednisole Vinblastine Phenobarbital St. John’s Wort		Use With Caution	There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort.
Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A: Hexobarbital Phenytoin Valproate		Use With Caution	There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.
Drugs that Affect Clarithromycin
Drug(s) that Affect the Pharmacokinetics of Clarithromycin	Recommendation		Comments
Antifungals: Itraconazole	Use With Caution		Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions (see also Itraconazole under “Drugs That Are Affected By Clarithromycin” in the table above).
Antivirals: Atazanavir Ritonavir (in patients with decreased renal function) Saquinavir (in patients with decreased renal function) Etravirine Saquinavir (in patients with normal renal function) Ritonavir (in patients with normal renal function)	Use With Caution No Dose Adjustment		Atazanavir: When clarithromycin is co-administered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology (12.3)]. Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors. Ritonavir: Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with ritonavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium [see Pharmacokinetics (12.3)]. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors. Saquinavir: When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (refer to ritonavir above) [see Pharmacokinetics (12.3)]. Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.
Proton Pump Inhibitors: Omeprazole	Use With Caution		Omeprazole: Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole [see Pharmacokinetics (12.3)].
Miscellaneous Cytochrome P450 Inducers: Efavirenz Nevirapine Rifampicin Rifabutin Rifapentine	Use With Caution		Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are Affected By Clarithromycin” in the table above).

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Figure 1: Effect of interacting drugs on the pharmacokinetics of venlafaxine and active metabolite O-desmethylvenlafaxine (ODV).

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 7. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug Name	Effect on Concentration of Amprenavir or Concomitant Drug	Clinical Comment
HCV/HIV-Antiviral Agents
HCV protease inhibitor: Boceprevir	LEXIVA: ↓Amprenavir (predicted) ↔ or ↓Boceprevir (predicted) LEXIVA/ritonavir: ↓Amprenavir (predicted) ↓Boceprevir (predicted)	Coadministration of LEXIVA or LEXIVA/ritonavir and boceprevir is not recommended.
HCV protease inhibitor: Simeprevir	LEXIVA: ↔Amprenavir (predicted) ↑ or ↓Simeprevir (predicted) LEXIVA/ritonavir: ↔Amprenavir (predicted) ↑Simeprevir (predicted)	Coadministration of LEXIVA or LEXIVA/ritonavir and simeprevir is not recommended.
HCV protease inhibitor: Paritaprevir (coformulated with ritonavir and ombitasvir and coadministered with dasabuvir)	LEXIVA: ↑Amprenavir (predicted) ↑ or ↔Paritaprevir (predicted) LEXIVA/ritonavir: ↑ or ↔Amprenavir (predicted) ↑Paritaprevir (predicted)	Appropriate doses of the combinations with respect to safety and efficacy have not been established. LEXIVA 1400 mg once daily may be considered when coadministered with paritaprevir/ritonavir/ombitasvir/ dasabuvir. Coadministration of LEXIVA/ritonavir and paritaprevir/ritonavir/ombitasvir/ dasabuvir is not recommended.
Non-nucleoside reverse transcriptase inhibitor: Efavirenz ^a	LEXIVA: ↓Amprenavir LEXIVA/ritonavir: ↓Amprenavir	Appropriate doses of the combinations with respect to safety and efficacy have not been established. An additional 100 mg/day (300 mg total) of ritonavir is recommended when efavirenz is administered with LEXIVA/ritonavir once daily. No change in the ritonavir dose is required when efavirenz is administered with LEXIVA plus ritonavir twice daily.
Non-nucleoside reverse transcriptase inhibitor: Nevirapine ^a	LEXIVA: ↓Amprenavir ↑Nevirapine LEXIVA/ritonavir: ↓Amprenavir ↑Nevirapine	Coadministration of nevirapine and LEXIVA without ritonavir is not recommended. No dosage adjustment required when nevirapine is administered with LEXIVA/ritonavir twice daily. The combination of nevirapine administered with LEXIVA/ritonavir once-daily regimen has not been studied.
HIV protease inhibitor: Atazanavir ^a	LEXIVA: Interaction has not been evaluated. LEXIVA/ritonavir: ↓Atazanavir ↔Amprenavir	Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitors: Indinavir ^a, nelfinavir ^a	LEXIVA: ↑Amprenavir Effect on indinavir and nelfinavir is not well established. LEXIVA/ritonavir: Interaction has not been evaluated.	Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitors: Lopinavir/ritonavir ^a	↓Amprenavir ↓Lopinavir	An increased rate of adverse events has been observed. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitor: Saquinavir ^a	LEXIVA: ↓Amprenavir Effect on saquinavir is not well established. LEXIVA/ritonavir: Interaction has not been evaluated.	Appropriate doses of the combination with respect to safety and efficacy have not been established.
HIV integrase inhibitor: Raltegravir ^a	LEXIVA: ↓Amprenavir ↓Raltegravir LEXIVA/ritonavir: ↓Amprenavir ↓Raltegravir	Appropriate doses of the combination with respect to safety and efficacy have not been established.
HIV integrase inhibitor: Dolutegravir ^a	LEXIVA/ritonavir: ↓Dolutegravir	The recommended dose of dolutegravir is 50 mg twice daily when coadministered with LEXIVA/ritonavir. Use an alternative combination where possible in patients with known or suspected integrase inhibitor resistance.
HIV CCR5 co-receptor antagonist: Maraviroc ^a	LEXIVA/ritonavir: ↓Amprenavir ↑Maraviroc	No dosage adjustment required for LEXIVA/ritonavir. The recommended dose of maraviroc is 150 mg twice daily when coadministered with LEXIVA/ritonavir. LEXIVA should be given with ritonavir when coadministered with maraviroc.
Other Agents
Antiarrhythmics: Amiodarone, lidocaine (systemic), and quinidine	↑Antiarrhythmics	Use with caution. Increased exposure may be associated with life-threatening reactions such as cardiac arrhythmias. Therapeutic concentration monitoring, if available, is recommended for antiarrhythmics.
Anticoagulant: Warfarin		Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: Carbamazepine, phenobarbital, phenytoin Phenytoin ^a	LEXIVA: ↓Amprenavir LEXIVA/ritonavir: ↑Amprenavir ↓Phenytoin	Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations in patients taking these agents concomitantly. Plasma phenytoin concentrations should be monitored and phenytoin dose should be increased as appropriate. No change in LEXIVA/ritonavir dose is recommended.
Antidepressant: Paroxetine, trazodone	↓Paroxetine ↑Trazodone	Any paroxetine dose adjustment should be guided by clinical effect (tolerability and efficacy). Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as LEXIVA, the combination should be used with caution and a lower dose of trazodone should be considered.
Antifungals: Ketoconazole ^a, itraconazole	↑Ketoconazole ↑Itraconazole	Increase monitoring for adverse events. LEXIVA: Dose reduction of ketoconazole or itraconazole may be needed for patients receiving more than 400 mg ketoconazole or itraconazole per day. LEXIVA/ritonavir: High doses of ketoconazole or itraconazole (greater than 200 mg/day) are not recommended.
Anti-gout: Colchicine	↑Colchicine	Patients with renal or hepatic impairment should not be given colchicine with LEXIVA/ritonavir. LEXIVA/ritonavir and coadministration of colchicine: Treatment of gout flares: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). LEXIVA and coadministration of colchicine: Treatment of gout flares: 1.2 mg (2 tablets) x 1 dose. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg twice a day or 0.6 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once a day. Treatment of FMF: Maximum daily dose of 1.2 mg (may be given as 0.6 mg twice a day).
Antimycobacterial: Rifabutin ^a	↑Rifabutin and rifabutin metabolite	A complete blood count should be performed weekly and as clinically indicated to monitor for neutropenia. LEXIVA: A dosage reduction of rifabutin by at least half the recommended dose is required. LEXIVA/ritonavir: Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (a maximum dose of 150 mg every other day or 3 times per week).
Antipsychotics: Quetiapine	LEXIVA/ritonavir: ↑Quetiapine	Initiation of LEXIVA with ritonavir in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine drug exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking LEXIVA with ritonavir: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
Lurasidone	↑Lurasidone	LEXIVA: If coadministration is necessary, reduce the lurasidone dose. Refer to the lurasidone prescribing information for concomitant use with moderate CYP3A4 inhibitors. LEXIVA/ritonavir: Use of lurasidone is contraindicated.
Benzodiazepines: Alprazolam, clorazepate, diazepam, flurazepam	↑Benzodiazepines	Clinical significance is unknown. A decrease in benzodiazepine dose may be needed.
Calcium channel blockers: Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine	↑Calcium channel blockers	Use with caution. Clinical monitoring of patients is recommended.
Corticosteroid: Dexamethasone	↓Amprenavir	Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations.
Endothelin-receptor antagonists: Bosentan	↑Bosentan	Coadministration of bosentan in patients on LEXIVA: In patients who have been receiving LEXIVA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Coadministration of LEXIVA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of LEXIVA. After at least 10 days following the initiation of LEXIVA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Histamine H ₂-receptor antagonists: Cimetidine, famotidine, nizatidine, ranitidine ^a	LEXIVA: ↓Amprenavir LEXIVA/ritonavir: Interaction not evaluated	Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations.
HMG-CoA reductase inhibitors: Atorvastatin ^a	↑Atorvastatin	Titrate atorvastatin dose carefully and use the lowest necessary dose; do not exceed atorvastatin 20 mg/day.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus	↑Immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents.
Inhaled beta-agonist: Salmeterol	↑Salmeterol	Concurrent administration of salmeterol with LEXIVA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Inhaled/nasal steroid: Fluticasone	LEXIVA: ↑Fluticasone LEXIVA/ritonavir: ↑Fluticasone	Use with caution. Consider alternatives to fluticasone, particularly for long-term use. May result in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone. Coadministration of fluticasone and LEXIVA/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
Narcotic analgesic: Methadone	↓Methadone	Data suggest that the interaction is not clinically relevant; however, patients should be monitored for opiate withdrawal symptoms.
Oral contraceptives: Ethinyl estradiol/norethindrone ^a	LEXIVA: ↓Amprenavir ↓Ethinyl estradiol LEXIVA/ritonavir: ↓Ethinyl estradiol	Alternative methods of non-hormonal contraception are recommended. May lead to loss of virologic response. ^a Increased risk of transaminase elevations. No data are available on the use of LEXIVA/ritonavir with other hormonal therapies, such as hormone replacement therapy (HRT) for postmenopausal women.
PDE5 inhibitors: Sildenafil, tadalafil, vardenafil	↑Sildenafil ↑Tadalafil ↑Vardenafil	May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Use of sildenafil (REVATIO) is contraindicated when used for the treatment of PAH [see Contraindications (4)]. The following dose adjustments are recommended for use of tadalafil (ADCIRCA ^®) with LEXIVA: Coadministration of ADCIRCA in patients on LEXIVA: In patients receiving LEXIVA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Coadministration of LEXIVA in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of LEXIVA. Stop ADCIRCA at least 24 hours prior to starting LEXIVA. After at least one week following the initiation of LEXIVA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: LEXIVA: Sildenafil: 25 mg every 48 hours. Tadalafil: no more than 10 mg every 72 hours. Vardenafil: no more than 2.5 mg every 24 hours. LEXIVA/ritonavir: Sildenafil: 25 mg every 48 hours. Tadalafil: no more than 10 mg every 72 hours. Vardenafil: no more than 2.5 mg every 72 hours. Use with increased monitoring for adverse events.
Proton pump inhibitors: Esomeprazole ^a, lansoprazole, omeprazole, pantoprazole, rabeprazole	LEXIVA: ↔Amprenavir ↑Esomeprazole LEXIVA/ritonavir: ↔Amprenavir ↔Esomeprazole	Proton pump inhibitors can be administered at the same time as a dose of LEXIVA with no change in plasma amprenavir concentrations.
Tricyclic antidepressants: Amitriptyline, imipramine	↑Tricyclics	Therapeutic concentration monitoring is recommended for tricyclic antidepressants.

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Table 18 Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Co-administered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
	Co-administered Drug	Risperidone	AUC	C_max
Enzyme (CYP2D6)Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-	Re-evaluate dosing. Do not exceed 8 mg/day
Enzyme (CYP3A/PgP inducers)Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A)Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed

Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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^aShould be administered at least 4 hours prior to WELCHOL
^bNo significant alteration of warfarin drug levels with warfarin and WELCHOL coadministration in an in vivo study which did not evaluate warfarin pharmacodynamics (INR). [See Post-marketing Experience (6.2)]
^c Cyclosporine levels should be monitored and, based on theoretical grounds, cyclosporine should be administered at least 4 hours prior to WELCHOL.
^dPatients receiving concomitant metformin ER and colesevelam should be monitored for clinical response as is usual for the use of anti-diabetes drugs.
Table 4 Drugs Tested in In Vitro Binding or In Vivo Drug Interaction Testing or With Post-Marketing Reports
Drugs with a known interaction with colesevelam: Decrease in exposure of coadministered drug	cyclosporine^c, glimepiride^a, glipizide^a, glyburide^a, levothyroxine^a, olmesartan medoxomil^a, and oral contraceptives containing ethinyl estradiol and norethindrone^a
Drugs with a known interaction with colesevelam: Increase in exposure of coadministered drug	metformin extended release (ER)^d
Drug(s) with postmarketing reports consistent with potential drug-drug interactions when coadministered with WELCHOL	phenytoin^a, warfarin^b
Drugs that do not interact with colesevelam based on in vitro or in vivo testing	aspirin, atenolol, cephalexin, ciprofloxacin, digoxin, enalapril, fenofibrate, lovastatin, metformin, metoprolol, phenytoin^a, pioglitazone, rosiglitazone, quinidine, repaglinide, sitagliptin, valproic acid, verapamil, warfarin^b

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( , , , ) 2.6 5.1 7 12.3
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.7, 5.1, 7.1, 7.2, 7.3, 7.6, 7.8)
Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, fibrates	Avoid VYTORIN
Cyclosporine, danazol	Do not exceed 10/10 mg VYTORIN daily
Amiodarone, verapamil	Do not exceed 10/20 mg VYTORIN daily
Diltiazem	Do not exceed 10/40 mg VYTORIN daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
* For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily*
Grapefruit juice	Avoid grapefruit juice

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Table 4: Established and Other Potentially Significant Drug Interactions: Alteration in CERDELGA Dosage May Be Recommended Based on Predicted Interaction in PMs
CYP450 Inhibitors	Recommended CERDELGA Dosage for PMs
Strong CYP3A inhibitors e.g., ketoconazole	Contraindicated
Moderate CYP3A inhibitors e.g., fluconazole	Not recommended
Weak CYP3A inhibitors e.g., ranitidine	Not recommended

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Interacting DrugInteracting Drug	InteractionInteraction
Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products ( 2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents	Carefully monitor blood glucose ( 5.12, 7.3)

Table name: Pimozide Clinical ImpactIncreased pimozide exposureInterventionaprepitant is contraindicated [see CONTRAINDICATIONS (4)]. Benzodiazepines Clinical ImpactIncreased exposure to midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) may increase the risk of adverse reactions [see CLINICAL PHARMACOLOGY (12.3)].Intervention125-mg/80-mg/80-mg aprepitant regimen • Monitor for benzodiazepine-related adverse reactions. • Depending on the clinical situation (e.g., elderly patients) and degree of monitoring available, reduce the dose of intravenous midazolam Single 40 mg dose of aprepitant • No dosage adjustment of the benzodiazepine needed Dexamethasone Clinical ImpactIncreased dexamethasone exposure [see CLINICAL PHARMACOLOGY (12.3)].Intervention125-mg/80-mg/80-mg aprepitant regimen • Reduce the dose of oral dexamethasone by approximately 50% [see DOSAGE AND ADMINISTRATION (2.1)]. Single 40 mg dose of aprepitant • No dosage adjustment of oral dexamethasone needed Methylprednisolone Clinical ImpactIncreased methylprednisolone exposure [see CLINICAL PHARMACOLOGY (12.3)].Intervention125-mg/80-mg/80-mg aprepitant regimen • Reduce the dose of intravenous methylprednisolone by approximately 25% • Reduce the dose of oral methylprednisolone by approximately 50% Single 40 mg dose of aprepitant • No dosage adjustment of methylprednisolone needed Chemotherapeutic agents that are metabolized by CYP3A4 Clinical ImpactIncreased exposure of the chemotherapeutic agent may increase the risk of adverse reactions [see CLINICAL PHARMACOLOGY (12.3)].InterventionVinblastine, vincristine, or ifosfamide or other chemotherapeutic agents • Monitor for chemotherapeutic-related adverse reactions. Etoposide, vinorelbine, paclitaxel, and docetaxel • No dosage adjustment needed. Hormonal Contraceptives Clinical ImpactDecreased hormonal exposure during administration of and for 28 days after administration of the last dose of aprepitant [see CLINICAL PHARMACOLOGY (12.3)].InterventionAlternative or back-up methods of contraception should be used during treatment with aprepitant and for 1 month following the last dose of aprepitantExamplesbirth control pills, skin patches, implants, and certain IUDsCYP2C9 Substrates Warfarin Clinical ImpactDecreased warfarin exposure and prolongation of prothrombin time (INR) [see CLINICAL PHARMACOLOGY (12.3)].InterventionIn patients on chronic warfarin therapy, monitor the prothrombin time (INR) in the 2-week period, particularly at 7 to 10 days, following initiation of the 125-mg/80-mg/80-mg aprepitant regimen with each chemotherapy cycle, or following administration of a single 40-mg dose of aprepitant.Other 5-HT3 Antagonists Clinical ImpactNo change in the exposure of the 5-HT3 antagonist [see CLINICAL PHARMACOLOGY (12.3)].InterventionNo dosage adjustment neededExamplesondansetron, granisetron, dolasetron


CYP3A4 Substrates

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors,boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily*
Grapefruit juice	Avoid grapefruit juice
*For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.

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Factors	Dosage Adjustments for Aripiprazole
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
Known CYP2D6 Poor Metabolizersand strong CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors	Administer half of usual dose
Strong CYP2D6 and CYP3A4inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double usual dose over 1 to 2 weeks

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CYP2C19 or CYP3A4 Inducers
Clinical Impact:	Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention:	St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions (5.9)]. Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:	Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
Intervention:	Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole.

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Diluent	Storage
Diluent	Room Temp. (25°C)	Refrigerated (4°C)
Sterile Water	2 days	10 days
0.9% Sodium Chloride Solution	2 days	10 days
5% Dextrose Solution	2 days	10 days
10% Dextrose Solution	2 days	10 days
5% Dextrose + 0.9% Sodium Chloride SolutionData available for 10 to 40 mg/mL concentrations in this diluent in PVC containers only.	2 days	Incompatible
5% Dextrose + 0.45% Sodium Chloride Solution	2 days	Incompatible

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Table 10 Drugs That Should Not Be Coadministered With VIRACEPT
Drug Class: Drug Name	Clinical Comment

Antiarrhythmics: amiodarone, quinidine	CONTRAINDICATED due to potential for serious and/or life threatening reactions such as cardiac arrhythmias.
Antimycobacterial: rifampin	May lead to loss of virologic response and possible resistance to VIRACEPT or other coadministered antiretroviral agents.
Ergot Derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine	CONTRAINDICATED due to potential for serious and/or life threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
Herbal Products: St. John's wort (hypericum perforatum)	May lead to loss of virologic response and possible resistance to VIRACEPT or other coadministered antiretroviral agents.
HMG-CoA Reductase Inhibitors: lovastatin, simvastatin	Potential for serious reactions such as risk of myopathy including rhabdomyolysis.
Neuroleptic: pimozide	CONTRAINDICATED due to potential for serious and/or life threatening reactions such as cardiac arrhythmias.
Proton Pump Inhibitors	Omeprazole decreases the plasma concentrations of nelfinavir. Concomitant use of proton pump inhibitors and VIRACEPT may lead to a loss of virologic response and development of resistance.
Sedative/Hypnotics: midazolam, triazolam	CONTRAINDICATED due to potential for serious and/or life threatening reactions such as prolonged or increased sedation or respiratory depression.

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Interacting DrugInteracting Drug	InteractionInteraction
Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products.
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Table 1: Clinically Significant Drug Interactions with Naproxen
Drugs That Interfere with Hemostasis
Clinical Impact:	Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of naproxen tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	Concomitant use of naproxen tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen tablets are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of naproxen tablets and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of naproxen tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention	During concomitant use of naproxen tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of naproxen tablets and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen tablets and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen tablets and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen tablets and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen tablets and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen tablets and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of naproxen tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen tablets are not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen tablets are not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxen tablets are not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen tablets and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:	Patients simultaneously receiving naproxen tablets and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

Table name:

Factors	Dosage Adjustments for Aripiprazole
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors	Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double usual dose over 1 to 2 weeks

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine (CBZ) and CBZ epoxide	? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2 fold.
Valproate	? valproate	Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table II. Clinically significant drug interactions with theophylline.Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
Drug	Type of Interaction	EffectAverage effect on steady-state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine	Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.
Alcohol	A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours.	30% increase
Allopurinol	Decreases theophylline clearance at allopurinol doses ≥600 mg/day.	25% increase
Aminoglutethimide	Increases theophylline clearance by induction of microsomal enzyme activity.	25% decrease
Carbamazepine	Similar to aminoglutethimide.	30% decrease
Cimetidine	Decreases theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase
Ciprofloxacin	Similar to cimetidine.	40% increase
Clarithromycin	Similar to erythromycin.	25% increase
Diazepam	Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.	Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram	Decreases theophylline clearance by inhibiting hydroxylation and demethylation.	50% increase
Enoxacin	Similar to cimetidine.	300% increase
Ephedrine	Synergistic CNS effects	Increased frequency of nausea, nervousness, and insomnia.
Erythromycin	Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen	Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.	30% increase
Flurazepam	Similar to diazepam.	Similar to diazepam.
Fluvoxamine	Similar to cimetidine.	Similar to cimetidine.
Halothane	Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.	Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A	Decreases theophylline clearance.	100% increase
Isoproterenol (IV)	Increase theophylline clearance.	20% increase
Ketamine	Pharmacologic	May lower theophylline seizure threshold.
Lithium	Theophylline increases renal lithium clearance.	Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam	Similar to diazepam.	Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.	20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine	Similar to disulfiram.	80% increase
Midazolam	Similar to diazepam.	Similar to diazepam.
Moricizine	Increases theophylline clearance.	25% decrease
Pancuronium	Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.	Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline	Decreases theophylline clearance.	30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.	25% decrease after two weeks of concurrent PB.
Phenytoin	Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.	Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone	Decreases theophylline clearance and pharmacologic interaction.	40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and pharmacologic interaction.	100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin	Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.	20 to 40% decrease
Sulfinpyrazone	Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.	20% increase
Tacrine	Similar to cimetidine, also increases renal clearance of theophylline.	90% increase
Thiabendazole	Decreases theophylline clearance.	190% increase
Ticlopidine	Decreases theophylline clearance.	60% increase
Troleandomycin	Similar to erythromycin.	33 to 100% increase depending on troleandomycin dose.
Verapamil	Similar to disulfiram.	20% increase

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Drugs That Interfere with Hemostasis
Clinical Impact:	Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of indomethacin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions ( 5.11 )].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions ( 5.2 ) ].
Intervention:	Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions ( 5.11 )].Indomethacin is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of indomethacin capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.During concomitant use of indomethacin capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions ( 5.6 )].When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.It has been reported that the addition of triamterene to a maintenance schedule of Indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together.Both indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently [ see Warnings and Precautions ( 5.6 )].
Intervention:	Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels. [ see Warnings and Precautions ( 5.6 )].
Digoxin
Clinical Impact:	The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention:	During concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions ( 5.2 )]. Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin [see Clinical Pharmacology ( 12.3 )].In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage.
Intervention:	The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Probenecid
Clinical Impact:	When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased.
Intervention:	During the concomitant use of indomethacin and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments.

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Table 7 Summary of AED Interactions with Oxcarbazepine Tablets, USP
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Tablets Dose (mg/day)	Influence of Oxcarbazepine Tablets on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400-2000	900	nc nc denotes a mean change of less than 10%	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100-150	600-1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250-500	600-1800 >1200-2400	nc ^, Pediatrics up to 40% increase Mean increase in adults at high oxcarbazepine tablets, USP doses [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400-2800	600-1800	nc	18% decrease [CI: 13% decrease, 40% decrease]

Table name:

Digoxin concentrations increased greater than 50%
	Digoxin Serum Concentration Increase	Digoxin AUC Increase	Recommendations
Quinidine	NA	54-83%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
Ritonavir	NA	86%
Digoxin concentrations increased less than 50%
Amiodarone	17%	40%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
Propafenone	28%	29%
Quinine	NA	34-38%
Spironolactone	NA	44%
Verapamil	NA	24%

Table name:

Drug	Description of Interaction
Tolbutamide; Sulfonylureas	Hypoglycemia potentiated
Methotrexate	Decreases tubular reabsorption; clinical toxicity from methotrexate can result
Oral Anticoagulants	Increased bleeding

Table name:

Table 2. Drugs That May Decrease T4 Absorption (Hypothyroidism)
Potential impact: Concurrent use may reduce the efficacy of SYNTHROID by binding and delaying or preventing absorption, potentially resulting in hypothyroidism.
Drug or Drug Class	Effect
Calcium Carbonate Ferrous Sulfate	Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer SYNTHROID at least 4 hours apart from these agents.
Orlistat	Monitor patients treated concomitantly with orlistat and SYNTHROID for changes in thyroid function.
Bile Acid Sequestrants - Colesevelam - Cholestyramine - Colestipol Ion Exchange Resins - Kayexalate - Sevelamer	Bile acid sequestrants and ion exchange resins are known to decrease levothyroxine absorption. Administer SYNTHROID at least 4 hours prior to these drugs or monitor TSH levels.
Other drugs: Proton Pump Inhibitors Sucralfate Antacids - Aluminum & Magnesium Hydroxides - Simethicone	Gastric acidity is an essential requirement for adequate absorption of levothyroxine. Sucralfate, antacids and proton pump inhibitors may cause hypochlorhydria, affect intragastric pH, and reduce levothyroxine absorption. Monitor patients appropriately.

Table name:

Digoxin concentrations increased greater than 50%
NA – Not available/reported
	Digoxin Serum Concentration Increase	Digoxin AUC Increase	Recommendations
Amiodarone	70%	NA	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30 to 50% or by modifying the dosing frequency and continue monitoring.
Captopril	58%	39%
Clarithromycin	NA	70%
Dronedarone	NA	150%
Gentamicin	129 to 212%	NA
Erythromycin	100%	NA
Itraconazole	80%	NA
Lapatinib	NA	180%
Nitrendipine	57%	15%
Propafenone	NA	60 to 270%
Quinidine	100%	NA
Ranolazine	50%	NA
Ritonavir	NA	86%
Telaprevir	50%	85%
Tetracycline	100%	NA
Verapamil	50 to 75%	NA
Digoxin concentrations increased less than 50%
Atorvastatin	22%	15%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15 to 30% or by modifying the dosing frequency and continue monitoring.
Carvedilol	16%	14%
Conivaptan	33%	43%
Diltiazem	20%	NA
Indomethacin	40%	NA
Nefazodone	27%	15%
Nifedipine	45%	NA
Propantheline	24%	24%
Quinine	NA	33%
Raberprazole	29%	19%
Saquinavir	27%	49%
Spironolactone	25%	NA
Telmisartan	20 to 49%	NA
Teicagrelor	31%	28%
Tolvaptan	30%	NA
Trimethoprim	22 to 28%	NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John's Wort, sucralfate, sulfasalazine			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20 to 40% as necessary.

•
Antiretrovirals
Clinical Impact:	The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
Intervention:	Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications (4)]. Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:	Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention:	Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact:	Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].
Intervention:	A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact:	Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)]. There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention:	Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6)].
Citalopram
Clinical Impact:	Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention:	Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:	Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].
Intervention:	Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:	Potential for increased exposure of phenytoin.
Intervention:	Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:	Increased exposure of diazepam [see Clinical Pharmacology (12.3)].
Intervention:	Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:	Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention:	Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:	Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:	Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)]. See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:	Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:	See Contraindications, Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact:	Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention:	Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:	Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10), Clinical Pharmacology (12.2)].
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:	Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact:	There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:	An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:	There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:	Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. ( 2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents	Carefully monitor blood glucose ( 5.12, 7.3)

Table name:

Table 2: Drug-Thyroidal Axis Interactions
	Drug or Drug Class		Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
		Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
		Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
		Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
		Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
		Amiodarone Iodide (including iodine- containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
	Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
	Drugs that may increase		Drugs that may decrease
	serum TBG concentration		serum TBG concentration
	Clofibrate		Androgens / Anabolic Steroids
	Estrogen-containing oral		Asparaginase
	contraceptives		Glucocorticoids
	Estrogens (oral)		Slow-Release Nicotinic Acid
	Heroin / Methadone
	5-Fluorouracil
	Mitotane
	Tamoxifen
	Drugs that may cause protein-binding site displacement
	Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)		Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
	Carbamazepine Hydantoins Phenobarbital Rifampin		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
	Drugs that may decrease T ₄ 5' - deiodinase activity
	Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)		Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, Ieading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
	Miscellaneous
	Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives		Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
	Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
	Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin		Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
	Cardiac Glycosides		Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
	Cytokines - Interferon-α - Interleukin-2		Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
	Growth Hormones - Somatrem - Somatropin		Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
	Ketamine		Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
	Methylxanthine Bronchodilators - (e.g., Theophylline)		Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
	Radiographic Agents		Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
	Sympathomimetics		Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
	Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics		These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name:

Antiretrovirals
Clinical Impact:	The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3)]. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)]. There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
Intervention:	Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications (4)]. Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:	Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention:	Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact:	Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].
Intervention:	A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact:	Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)]. There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention:	Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6)].
Citalopram
Clinical Impact:	Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention:	Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:	Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].
Intervention:	Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:	Potential for increased exposure of phenytoin.
Intervention:	Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:	Increased exposure of diazepam [see Clinical Pharmacology (12.3)].
Intervention:	Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:	Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention:	Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:	Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:	Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)]. See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:	Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated.
	Amoxicillin also has drug interactions.
Intervention:	See Contraindications, Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact:	Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention:	Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:	Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10), Clinical Pharmacology (12.2)].
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:	Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact:	There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:	An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:	There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:	Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.

Table name:

Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone.

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidibetic agents	Carefully monitor blood glucose (5.11, 7.3)

Table name:

Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)	Do not exceed 40 mg atorvastatin daily

Table name:

Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
* Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing.
	20 mg/day	4 mg/day	1.6	-	Do not exceed 8 mg/day
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed

Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

Table name:

Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name:

Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T ₄ and T ₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT ₄. Continued administration results in a decrease in serum T ₄ and normal FT ₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T ₄ and T ₃ to TBG and transthyretin. An initial increase in serum FT ₄, is followed by return of FT ₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T ₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T ₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T ₄ to T ₃, leading to decreased T ₃ levels. However, serum T ₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T ₃ and T ₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T ₃ concentrations by 30% with minimal change in serum T ₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T ₃ and T ₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name:

AED Coadministered	AED Concentration	Topiramate Concentration
^a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. ^b = Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. NE = Not Evaluated
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

Table name:

Antibiotics	Anticonvulsants	Other Drugs/Dietary Supplements
nafcillin rifampin	carbamazepine oxcarbazepine phenobarbital phenytoin	bosentan octreotide orlistat sulfinpyrazone terbinafine ticlopidine	St. John’s Wort

Table name:

Table II. Clinically significant drug interactions with theophylline*.
Drug	Type of Interaction	Effect†
* Refer to PRECAUTIONS, Drug Interactions for further information regarding table. † Average effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine	Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.
Alcohol	A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours.	30% increase
Allopurinol	Decreases theophylline clearance at allopurinol doses ≥600 mg/day.	25% increase
Aminoglutethimide	Increases theophylline clearance by induction of microsomal enzyme activity.	25% decrease
Carbamazepine	Similar to aminoglutethimide.	30% decrease
Cimetidine	Decreases theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase
Ciprofloxacin	Similar to cimetidine.	40% increase
Clarithromycin	Similar to erythromycin.	25% increase
Diazepam	Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.	Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram	Decreases theophylline clearance by inhibiting hydroxylation and demethylation.	50% increase
Enoxacin	Similar to cimetidine.	300% increase
Ephedrine	Synergistic CNS effects.	Increased frequency of nausea, nervousness, and insomnia.
Erythromycin	Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen	Estrogen containing oral contraceptives decrease theophylline clearance in a dose- dependent fashion. The effect of progesterone on theophylline clearance is unknown.	30% increase
Flurazepam	Similar to diazepam.	Similar to diazepam.
Fluvoxamine	Similar to cimetidine.	Similar to cimetidine
Halothane	Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.	Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A	Decreases theophylline clearance.	100% increase
Isoproterenol (IV)	Increases theophylline clearance.	20% decrease
Ketamine	Pharmacologic.	May lower theophylline seizure threshold.
Lithium	Theophylline increases renal lithium clearance.	Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam	Similar to diazepam.	Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.	20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine	Similar to disulfiram.	80% increase
Midazolam	Similar to diazepam.	Similar to diazepam.
Moricizine	Increases theophylline clearance.	25% decrease
Pancuronium	Theophylline may antagonize non-depolarizing neuromuscular blocking effects, possibly due to phosphodiesterase inhibition.	Larger dose of pancuronium may be required to achieve neuromuscular blockade
Pentoxifylline	Decreases theophylline clearance.	30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.	25% decrease after two weeks of concurrent PB.
Phenytoin	Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.	Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone	Decreases theophylline clearance and pharmacologic interaction.	40% increase. Beta₂ blocking effect may decrease efficacy of theophylline
Propranolol	Similar to cimetidine and pharmacologic interaction.	100% increase. Beta₂ blocking effect may decrease efficacy of theophylline
Rifampin	Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.	20-40% decrease
St. John's Wort (Hypericum Perforatum)	Decrease in theophylline plasma concentrations.	Higher doses of theophylline may be required to achieve desired effect. Stopping St. John's Wort may result in theophylline toxicity.
Sulfinpyrazone	Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.	20% decrease
Tacrine	Similar to cimetidine, also increases renal clearance of theophylline.	90% increase
Thiabendazole	Decreases theophylline clearance.	190% increase
Ticlopidine	Decreases theophylline clearance.	60% increase
Troleandomycin	Similar to erythromycin.	33-100% increase depending on troleandomycin dose.
Verapamil	Similar to disulfiram.	20% increase

Table name:

Factors	Dosage Adjustments for Aripiprazole
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors	Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double usual dose over 1 to 2 weeks

Table name:

Bleeding times
Clinical Impact:	Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention:	This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact:	The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention:	Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact:	Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention:	This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.12, 7.3)

Table name:

Effects on Steady-State Fexofenadine Pharmacokinetics After 7 Days of Co-Administration with Fexofenadine Hydrochloride 120 mg Every 12 Hours (two times the recommended twice daily dose) in Healthy Volunteers (n=24)
Concomitant Drug	C_{max SS} (Peak plasma concentration)	AUC_SS(0–12h) (Extent of systemic exposure)
Erythromycin (500 mg every 8 hrs)	+82%	+109%
Ketoconazole (400 mg once daily)	+135%	+164%

Table name:

Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
↓= Decreased (induces lamotrigine gluronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ?= Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
	? CBZ epoxide	May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

Table name: Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.During concomitant use of diclofenac sodium delayed-release tablets and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of diclofenac sodium delayed-release tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS: Renal Toxicity and Hyperkalemia ). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.

Table 2. Clinically Significant Drug Interactions with Diclofenac
Drugs That Interfere with Hemostasis
Clinical Impact:
Intervention:	Monitor patients with concomitant use of diclofenac sodium delayed-release tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS: Hematologic Toxicity ).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ).
Intervention:	Concomitant use of diclofenac sodium delayed-release tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS: Hematologic Toxicity ). Diclofenac sodium delayed-release tablets are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:
Intervention:
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS: Renal Toxicity and Hyperkalemia ).
Digoxin
Clinical Impact:	The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of diclofenac sodium delayed-release tablets and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ).
Intervention:	The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of diclofenac sodium delayed-release tablets and pemetrexed may increase the risk of pemetrexed‑ associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or Inducers:
Clinical Impact:	Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Co-administration of diclofenac with CYP2C9 inhibitors (e.g. voriconazole) may enhance the exposure and toxicity of diclofenac whereas co‑administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of diclofenac.
Intervention:	A dosage adjustment may be warranted when diclofenac is administered with CYP2C9 inhibitors or inducers (see CLINICAL PHARMACOLOGY: Pharmacokinetics ).

Table name:

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

Table name:

Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.6).]
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported . Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [see Adverse Reactions (6.1).]
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution 2-fold increase in exposure	Monitor for sildenafil toxicity (see Pharmacokinetics -(12.3)-] .
Duloxetine	Avoid Use 5-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx ^® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2)].	Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

Table name: Use of sildenafil (Revatio) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications (4.2)].

The following dose adjustments are recommended for use of tadalafil (Adcirca) with APTIVUS/ritonavir: Co-administration of tadalafil (Adcirca) in patients on APTIVUS/ritonavir:

In patients receiving APTIVUS/ritonavir for at least one week, start Adcirca at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Co-administration of APTIVUS/ritonavir in patients on tadalafil (Adcirca):

Avoid use of tadalafil (Adcirca) during the initiation of APTIVUS/ritonavir. Stop Adcirca at least 24 hours prior to starting APTIVUS/ritonavir. After at least one week following the initiation of APTIVUS/ritonavir, resume Adcirca at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.


↑ increase, ↓ decrease, ↔ no change, ↕ unable to predict
Concomitant Drug Class: Drug name	Effect on Concentration of Tipranavir or Concomitant Drug	Clinical Comment
HIV-1 Antiviral Agents
Fusion Inhibitors:
Enfuvirtide	↑ Tipranavir	At steady state, tipranavir trough concentrations were approximately 45% higher in patients co-administered enfuvirtide in the Phase 3 trials. The mechanism for this increase is not known. Dose adjustments are not recommended.
Non-Nucleoside Reverse Transcriptase
Inhibitors:
Etravirine	↓ Etravirine	APTIVUS/ritonavir when coadministered with etravirine may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of etravirine. Etravirine and APTIVUS/ritonavir should not be coadministered.

Rilpivirine	The use of rilpivirine co-administered with APTIVUS/ritonavir has not been studied.	Concomitant use of rilpivirine with Aptivus/ritonavir may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Rilpivirine is not expected to affect the plasma concentrations of Aptivus/ritonavir.

Nucleoside Reverse Transcriptase
Inhibitors:
Abacavir	↓ Abacavir AUC by approximately 40%	Clinical relevance of reduction in abacavir levels not established. Dose adjustment of abacavir cannot be recommended at this time.

Didanosine (EC)	↓ Didanosine	Clinical relevance of reduction in didanosine levels not established. For optimal absorption, didanosine should be separated from APTIVUS/ritonavir dosing by at least 2 hours.

Zidovudine	↓ Zidovudine AUC by approximately 35%. ZDV glucuronide concentrations were unaltered.	Clinical relevance of reduction in zidovudine levels not established. Dose adjustment of zidovudine cannot be recommended at this time.
Protease Inhibitors (co-administered with 200 mg of ritonavir):
Fosamprenavir Lopinavir Saquinavir	↓ Amprenavir ↓ Lopinavir ↓ Saquinavir	Combining a protease inhibitor with APTIVUS/ritonavir is not recommended.
Protease Inhibitors (co-administered with 100 mg of ritonavir):
Atazanavir	↓ Atazanavir ↑ Tipranavir
Virus Integrase Strand Transfer Inhibitors:
Raltegravir	↓ Raltegravir	APTIVUS/ritonavir reduces plasma concentrations of raltegravir. Since comparable efficacy was observed for this combination in phase 3 studies, dose adjustment is not recommended.
Agents for Opportunistic Infections
Antifungals:
Fluconazole Itraconazole Ketoconazole Voriconazole	↑ Tipranavir, ↔ Fluconazole	Fluconazole increases tipranavir concentrations but dose adjustments are not needed. Fluconazole doses >200 mg/day are not recommended.
	↑ Itraconazole (not studied)
	↑ Ketoconazole (not studied)	Based on theoretical considerations itraconazole and ketoconazole should be used with caution. High doses (>200 mg/day) are not recommended.
	↕ Voriconazole (not studied)
		Due to multiple enzymes involved with voriconazole metabolism, it is difficult to predict the interaction.
Antimycobacterials:
Clarithromycin	↑ Tipranavir, ↑ Clarithromycin, ↓ 14-hydroxy-clarithromycin metabolite	No dose adjustment of APTIVUS or clarithromycin for patients with normal renal function is necessary.
		For patients with renal impairment the following dosage adjustments should be considered: For patients with CL_CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CL_CR <30 mL/min the dose of clarithromycin should be decreased by 75%.
Rifabutin	Tipranavir not changed, ↑ Rifabutin ↑ Desacetyl-rifabutin	Single dose study. Dosage reductions of rifabutin by 75% are recommended (e.g., 150 mg every other day). Increased monitoring for adverse events in patients receiving the combination is warranted. Further dosage reduction may be necessary.
Other Agents Commonly Used
Anticonvulsants:
Carbamazepine Phenobarbital Phenytoin	↓ Tipranavir	Caution should be used when prescribing carbamazepine, phenobarbital and/or phenytoin. APTIVUS may be less effective due to decreased tipranavir plasma concentration in patients taking these agents concomitantly.

Valproic Acid	↓ Valproic Acid	Caution should be used when prescribing valproic acid. Valproic acid may be less effective due to decreased valproic acid plasma concentration in patients taking APTIVUS concomitantly.
Antidepressants:

Trazodone	↑ Trazodone	Concomitant use of trazodone and APTIVUS/ritonavir may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP 3A4 inhibitor such as APTIVUS/ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.

Desipramine	Combination with APTIVUS/ritonavir not studied ↑ Desipramine	Dosage reduction and concentration monitoring of desipramine is recommended.

Selective Serotonin-Reuptake Inhibitors:	Combination with APTIVUS/ritonavir not studied	Antidepressants have a wide therapeutic index, but doses may need to be adjusted upon initiation of APTIVUS/ritonavir therapy.
Fluoxetine Paroxetine Sertraline	↑ Fluoxetine ↑ Paroxetine ↑ Sertraline
Anti-HCV agents:

Boceprevir	Co-administration of APTIVUS and boceprevir has not been studied.	With concomitant use, changes in exposure were observed both for boceprevir and certain protease inhibitors used for the treatment of HIV-1 infection or either medication. Information is not available regarding tipranavir or boceprevir exposure with concomitant use. It is not recommended to co-administer boceprevir with APTIVUS/ritonavir.
Telaprevir	Co-administration of APTIVUS and telaprevir has not been studied.	With concomitant use, changes in exposure were observed both for telaprevir and certain protease inhibitors used for the treatment of HIV-1 infection or telaprevir. Information is not available regarding tipranavir or telaprevir exposure with concomitant use. It is not recommended to co-administer telaprevir with APTIVUS/ritonavir.

Anti-gout:

Colchicine	↑ Colchicine	In patients with renal or hepatic impairment, coadministration of colchicine in patients on APTIVUS/ritonavir is contraindicated. In combination with APTIVUS/ritonavir, the following dosage adjustments are recommended in patients with normal renal and hepatic function: Treatment of gout flares: Co-administration of colchicine in patients on APTIVUS/ritonavir: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares: Co-administration of colchicine in patients on APTIVUS/ritonavir : If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF): Co-administration of colchicine in patients on APTIVUS/ritonavir: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antipsychotics:

Quetiapine	↑ Quetiapine	Initiation of APTIVUS with ritonavir in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking APTIVUS with ritonavir: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.

Benzodiazepines:

Parenterally administered midazolam	↑ Midazolam	Midazolam is extensively metabolized by CYP 3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, APTIVUS should not be given with orally administered midazolam [ see Contraindications (4) ]. If APTIVUS is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustments should be considered.
Buprenorphine/naloxone	↔ Buprenorphine ↓ Tipranavir	APTIVUS/ritonavir did not result in changes in the clinical efficacy of buprenorphine/naloxone. Compared to historical controls tipranavir C_min was decreased approximately 40% with this combination. Dose adjustments cannot be recommended.
Calcium Channel Blockers: Diltiazem Felodipine Nicardipine Nisoldipine Verapamil	Combination with APTIVUS/ritonavir not studied. Cannot predict effect of TPV/ritonavir on calcium channel blockers that are dual substrates of CYP3A and P-gp due to conflicting effect of TPV/ritonavir on CYP3A and P-gp. ↕ Diltiazem ↑ Felodipine (CYP3A substrate but not P-gp substrate) ↕ Nicardipine ↕ Nisoldipine (CYP3A substrate but not clear whether it is a P-gp substrate) ↕ Verapamil	Caution is warranted and clinical monitoring of patients is recommended.
Disulfiram/Metronidazole	Combination with TPV/ritonavir not studied	APTIVUS capsules contain alcohol that can produce disulfiram-like reactions when co-administered with disulfiram or other drugs which produce this reaction (e.g., metronidazole).
Endothelin receptor antagonists Bosentan	↑ Bosentan	Co-administration of bosentan in patients on APTIVUS/ritonavir: In patients who have been receiving APTIVUS/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Co-administration of APTIVUS/ritonavir in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of APTIVUS/ritonavir. After at least 10 days following the initiation of APTIVUS/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

HMG-CoA Reductase Inhibitors:
Atorvastatin Rosuvastatin	↑ Atorvastatin ↓ Hydroxy-atorvastatin metabolites ↑ Rosuvastatin	Avoid co-administration with atorvastatin.
Hypoglycemics:
	Combination with APTIVUS/ritonavir not studied	Careful glucose monitoring is warranted.

Glimepiride Glipizide Glyburide Pioglitazone	↔ Glimepiride (CYP 2C9) ↔ Glipizide (CYP 2C9) ↔ Glyburide (CYP 2C9) ↕ Pioglitazone (CYP 2C8 and CYP 3A4)
Repaglinide	↕ Repaglinide (CYP 2C8 and CYP 3A4)
Tolbutamide	↔ Tolbutamide (CYP 2C9) The effect of TPV/ritonavir on CYP 2C8 substrate is not known.
Immunosuppressants:
	Combination with APTIVUS/ritonavir not studied. Cannot predict effect of TPV/ritonavir on immunosuppressants due to conflicting effect of TPV/ritonavir on CYP 3A and P-gp.	Increased frequency of monitoring of plasma levels of immunosuppressant drugs is recommended.
Cyclosporine Sirolimus Tacrolimus	↕ Cyclosporine ↕ Sirolimus ↕ Tacrolimus
Inhaled beta agonist: Salmeterol	↑ Salmeterol	Concurrent administration of APTIVUS/ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Inhaled/Nasal Steroids:
Fluticasone	↑ Fluticasone	Concomitant use of fluticasone propionate and APTIVUS/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Co-administration of fluticasone propionate and APTIVUS/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
Narcotic Analgesics:
	Combinations with APTIVUS/ritonavir not studied	Dosage increase and long-term use of meperidine are not recommended due to increased concentrations of the metabolite normeperidine which has both analgesic activity and CNS stimulant activity (e.g., seizures).
Meperidine	↓ Meperidine, ↑ Normeperidine

Methadone	↓ Methadone ↓ S-Methadone, ↓ R-Methadone	Dosage of methadone may need to be increased when co-administered with APTIVUS and 200 mg of ritonavir.
Oral Contraceptives/Estrogens:
Ethinyl estradiol	↓ Ethinyl estradiol concentrations by 50%	Alternative methods of nonhormonal contraception should be used when estrogen based oral contraceptives are co-administered with APTIVUS and 200 mg of ritonavir. Patients using estrogens as hormone replacement therapy should be clinically monitored for signs of estrogen deficiency. Women using estrogens may have an increased risk of non-serious rash.
Proton Pump Inhibitors:
Omeprazole	↓ Omeprazole, ↔ Tipranavir	Dosage of omeprazole may need to be increased when co-administered with APTIVUS and ritonavir.

PDE-5 Inhibitors:
Sildenafil Tadalafil Vardenafil	Only the combination of tadalafil with APTIVUS/ritonavir has been studied (at doses used for treatment of erectile dysfunction).	Co-administration with APTIVUS/ritonavir may result in an increase in PDE-5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism.
	↑ Sildenafil (not studied) ↑ Tadalafil with first dose APTIVUS/ritonavir ↔ Tadalafil at APTIVUS/ritonavir steady-state ↑ Vardenafil (not studied)	Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH):
		Use of PDE-5 inhibitors for erectile dysfunction: Concomitant use of PDE-5 inhibitors with APTIVUS/ritonavir should be used with caution and in no case should the starting dose of: sildenafil exceed 25 mg within 48 hours tadalafil exceed 10 mg every 72 hours vardenafil exceed 2.5 mg every 72 hours Use with increased monitoring for adverse events.
Warfarin	↔ S-Warfarin	Frequent INR (international normalized ratio) monitoring upon initiation of APTIVUS/ritonavir therapy.

Table name:

Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine concentrations approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine and carbamazepine epoxide	? carbamazepine epoxide	May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

Table name:

Drugs That Interfere with Hemostasis
Clinical Impact:	● Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. ● Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of celecoxib with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2) ]. In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200-400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100-325 mg).
Intervention:	Concomitant use of celecoxib and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11) ]. Celecoxib is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	● NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). ● In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	● During concomitant use of celecoxib and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. ● During concomitant use of celecoxib and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. ● When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of celecoxib with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact:	The concomitant use of celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of celecoxib and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of celecoxib and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Celecoxib has no effect on methotrexate pharmacokinetics.
Intervention:	During concomitant use of celecoxib and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of celecoxib and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of celecoxib and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2) ].
Intervention:	The concomitant use of celecoxib with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of celecoxib and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of celecoxib and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or inducers
Clinical Impact:	Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g., fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g., rifampin) may lead to compromised efficacy of celecoxib.
Intervention:	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [see Clinical Pharmacology (12.3) ].
CYP2D6 substrates
Clinical Impact:	In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g., atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs.
Intervention	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [see Clinical Pharmacology (12.3)].
Corticosteroids
Clinical Impact:	Concomitant use of corticosteroids with celecoxib may increase the risk of GI ulceration or bleeding.
Intervention	Monitor patients with concomitant use of celecoxib with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2) ].

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Factors	Dosage Adjustments for Aripiprazole
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors	Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double usual dose over 1 to 2 weeks

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Drug Name	Effect on Concentration of Nevirapine or Concomitant Drug	Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir*	↓ Atazanavir ↑ Nevirapine	Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir*	↓Amprenavir ↑Nevirapine	Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir*	↓Amprenavir ↑Nevirapine	No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir*	↓ Indinavir	The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/ Ritonavir*	↓Lopinavir	Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir*	↓Nelfinavir M8 Metabolite ↓Nelfinavir C_min	The appropriate doses of the combination of nevirapine and nelfinavir, with respect to safety and efficacy, have not been established.
Saquinavir/ritonavir	The interaction between nevirapine and saquinavir/ritonavir has not been evaluated	The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz*	↓ Efavirenz	The appropriate doses of these combinations with respect to safety and efficacy have not been established.
Delavirdine Etravirine Rilpivirine		Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.
Hepatitis C Antiviral Agents
Boceprevir	Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine.	Nevirapine and boceprevir should not be coadministered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy.
Telaprevir	Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir.	Nevirapine and telaprevir should not be coadministered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events.
Other Agents
Analgesics:
Methadone*	↓ Methadone	Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics :
Amiodarone, disopyramide, lidocaine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Antibiotics:
Clarithromycin*	↓ Clarithromycin ↑ 14-OH clarithromycin	Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Rifabutin*	↑Rifabutin	Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin*	↓ Nevirapine	Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants:
Carbamazepine, clonazepam, ethosuximide	Plasma concentrations of nevirapine and the anticonvulsant may be decreased.	Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals:
Fluconazole*	↑Nevirapine	Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Ketoconazole*	↓ Ketoconazole	Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Itraconazole	↓ Itraconazole	Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics :
Warfarin	Plasma concentrations may be increased.	Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers:
Diltiazem, nifedipine, verapamil	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Cancer chemotherapy:
Cyclophosphamide	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Ergot alkaloids:
Ergotamine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Immunosuppressants :
Cyclosporine, tacrolimus, sirolimus	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Motility agents:
Cisapride	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Opiate agonists:
Fentanyl	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Oral contraceptives:
Ethinyl estradiol and Norethindrone*	↓ Ethinyl estradiol ↓ Norethindrone	Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.

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Factors	Adjusted Dose
CYP2D6 Poor Metabolizers
CYP2D6 Poor Metabolizers taking concomitant CYP3A4 inhibitors	200 mg200 mg and 160 mg dose adjustments are obtained only by using the 300 mg or 400 mg strength vials.
Patients Taking 400 mg of ABILIFY MAINTENA
Strong CYP2D6 or CYP3A4 inhibitors	300 mg
CYP2D6 and CYP3A4 inhibitors	200 mg
CYP3A4 inducers	Avoid use
Patients Taking 300 mg of ABILIFY MAINTENA
Strong CYP2D6 or CYP3A4 inhibitors	200 mg
CYP2D6 and CYP3A4 inhibitors	160 mg
CYP3A4 inducers	Avoid use

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DRUG	DESCRIPTION OF INTERACTION
Sulfonylureas	Hypoglycemia potentiated.
Methotrexate	Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants	Increased bleeding.

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine (CBZ) and CBZ epoxide	? CBZ epoxide	May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2 fold.
Valproate	? valproate	Decreased valproate concentrations an average of 25% over a 3 week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol,	famotidine	nizatidine
systemic and inhaled	felodipine	norfloxacin
amoxicillin	finasteride	ofloxacin
ampicillin,	hydrocortisone	omeprazole
with or without	isoflurane	prednisone, prednisolone
sulbactam	isoniazid	ranitidine
atenolol	isradipine	rifabutin
azithromycin	influenza vaccine	roxithromycin
caffeine,	ketoconazole	sorbitol
dietary ingestion	lomefloxacin	(purgative doses do not
cefaclor	mebendazole	inhibit theophylline
co-trimoxazole	medroxyprogesterone	absorption)
(trimethoprim and	methylprednisolone	sucralfate
sulfamethoxazole)	metronidazole	terbutaline, systemic
diltiazem	metoprolol	terfenadine
dirithromycin	nadolol	tetracycline
enflurane	nifedipine	tocainide

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Interacting Drug	Interaction
Multivalent cation-containing product including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Factors	Dosage Adjustment of aripiprazole
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors	Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double usual dose over 1 to 2 weeks

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Table 2. Clinically Significant Drug Interactions with Diclofenac
Drugs That Interfere with Hemostasis
Clinical Impact:	Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of diclofenac sodium delayed-release tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS: Hematologic Toxicity ).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ).
Intervention:	Concomitant use of diclofenac sodium delayed-release tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS: Hematologic Toxicity ). Diclofenac sodium delayed-release tablets are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of diclofenac sodium delayed-release tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS: Renal Toxicity and Hyperkalemia ). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS: Renal Toxicity and Hyperkalemia ).
Digoxin
Clinical Impact:	The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance . The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of diclofenac sodium delayed-release tablets and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ) .
Intervention:	The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of diclofenac sodium delayed-release tablets and pemetrexed may increase the risk of pemetrexed‑ associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or Inducers:
Clinical Impact:	Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Co-administration of diclofenac with CYP2C9 inhibitors (e.g. voriconazole) may enhance the exposure and toxicity of diclofenac whereas co‑administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of diclofenac.
Intervention:	A dosage adjustment may be warranted when diclofenac is administered with CYP2C9 inhibitors or inducers (see CLINICAL PHARMACOLOGY: Pharmacokinetics ).

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Interacting Agents	Prescribing Recommendations
Cyclosporine	Do not exceed 10 mg atorvastatin daily
Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir)	Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used.

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Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs that Interfere with Hemostasis
Clinical Impact :	Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention :	Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions ( 5 . 11)].
Aspirin
Clinical Impact :	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions ( 5 . 2)].
Intervention :	Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions ( 5 . 11)]. Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors , Angiotensin Receptor Blockers , or Beta - Blockers
Clinical Impact :	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention :	During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions ( 5 . 6 )]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact :	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention :	During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see Warnings and Precautions ( 5 . 6)].
Lithium
Clinical Impact :	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [ see Clinical Pharmacology ( 12 . 3)].
Intervention :	During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact :	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention :	During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact :	Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention :	During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact :	Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions ( 5 . 2)].
Intervention :	The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact :	Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention :	During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.

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Bleeding times
Clinical Impact:	Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention:	This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact:	The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention:	Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact:	Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention:	This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.

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Inhibitors of CYP2D6
Clinical Impact:	The concomitant use of tramadol hydrochloride extended-release tablets and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride extended-release tablets is achieved. Since M1 is a more potent µ-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease and the M1 plasma concentration will increase which could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, and may cause potentially fatal respiratory depression [see Clinical Pharmacology ( 12.3)] .
Intervention:	If concomitant use of a CYP2D6 inhibitor is necessary, follow patients closely for adverse reactions including opioid withdrawal, seizures, and serotonin syndrome. If a CYP2D6 inhibitor is discontinued, consider lowering tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved. Follow patients closely for adverse events including respiratory depression and sedation.
Examples	Quinidine, fluoxetine, paroxetine and bupropion
Inhibitors of CYP3A4
Clinical Impact:	The concomitant use of tramadol hydrochloride extended-release tablets and CYP3A4 inhibitors can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1. Follow patients closely for increased risk of serious adverse events including seizures and serotonin syndrome, and adverse reactions related to opioid toxicity including potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride extended-release tablets is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease [see Clinical Pharmacology ( 12.3)] , resulting in decreased opioid efficacy and possibly signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol.
Intervention:	If concomitant use is necessary, consider dosage reduction of tramadol hydrochloride extended-release tablets until stable drug effects are achieved. Follow patients closely for seizures and serotonin syndrome, and signs of respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved and follow patients for signs and symptoms of opioid withdrawal.
Examples	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact:	The concomitant use of tramadol hydrochloride extended-release tablets and CYP3A4 inducers can decrease the plasma concentration of tramadol [see Clinical Pharmacology ( 12.3)] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol, [see Warnings and Precautions ( 5.4)] . After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase [see Clinical Pharmacology ( 12.3)] , which could increase or prolong both the therapeutic effects and adverse reactions, and may cause seizures and serotonin syndrome, and potentially fatal respiratory depression.
Intervention:	If concomitant use is necessary, consider increasing the tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved. Follow patients for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider tramadol hydrochloride extended-release tablets dosage reduction and monitor for seizures and serotonin syndrome, and signs of sedation and respiratory depression. Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of tramadol hydrochloride extended-release tablets and carbamazepine is not recommended.
Examples:	Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions ( 5.5)] .
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome .
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue tramadol hydrochloride extended-release tablets if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions ( 5.6)] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions ( 5.2)].
Intervention:	Do not use tramadol hydrochloride extended-release tablets in patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of tramadol hydrochloride extended-release tablets and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Tramadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of tramadol hydrochloride extended-release tablets and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when tramadol hydrochloride extended-release tablets are used concomitantly with anticholinergic drugs.
Digoxin
Clinical Impact:	Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity.
Intervention:	Follow patients for signs of digoxin toxicity and adjust the dosage of digoxin as needed.
Warfarin
Clinical Impact:	Post-marketing surveillance of tramadol has revealed rare reports of alteration of warfarin effect, including elevation of prothrombin times.
Intervention:	Monitor the prothrombin time of patients on warfarin for signs of an interaction and adjust the dosage of warfarin as needed.

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Bleeding times
Clinical Impact:	Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention:	This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact:	The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention:	Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact:	Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention:	This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.

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Table 4: Clinically Relevant Interactions Affecting Omeprazole When Co-Administered with Other Drugs
CYP2C19 or CYP3A4 Inducers
Clinical Impact:	Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention:	St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions (5.9)]. Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:	Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
Intervention:	Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole.

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Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs that Interfere with Hemostasis
Clinical Impact :	Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention :	Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions ( 5 . 11)].
Aspirin
Clinical Impact :	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions ( 5 . 2)].
Intervention :	Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions ( 5 . 11)]. Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors , Angiotensin Receptor Blockers , or Beta - Blockers
Clinical Impact :	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention :	During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions ( 5 . 6 )]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact :	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention :	During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see Warnings and Precautions ( 5 . 6)].
Lithium
Clinical Impact :	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [ see Clinical Pharmacology ( 12 . 3)].
Intervention :	During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact :	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention :	During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact :	Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention :	During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact :	Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions ( 5 . 2)].
Intervention :	The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact :	Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention :	During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.

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Table 9: Drugs That are Affected by and Affecting Ciprofloxacin Tablets
Drugs That are Affected by Ciprofloxacin Tablets
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin tablets is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline	Avoid use (Plasma exposure likely to be increased and prolonged)	Concurrent administration of ciprofloxacin tablets with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.9) ].
Drugs Known to Prolong QT Interval	Avoid use	Ciprofloxacin tablets may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.11) and Use in Specific Populations (8.5)].
Oral Antidiabetic Drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin tablets and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were coadministered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin tablets are co-administered with oral antidiabetic drugs [see Adverse Reactions (6.1)].
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin tablets discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin tablets with phenytoin.
Cyclosporine	Use with caution (Transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin tablets are co-administered with cyclosporine.
Anticoagulant Drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin tablets to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin tablets with an oral anticoagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin tablets therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin tablets [see Warnings and Precautions (5.16) ].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin tablets are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution 2-fold increase in exposure	Monitor for sildenafil toxicity [see Clinical Pharmacology (12.3) ].
Duloxetine	Avoid use 5-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity.
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin tablets inhibit the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin Tablets
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx^® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin tablets should be taken at least 2 hours before or 6 hours after multivalent cation-containing products administration [see Dosage and Administration (2.4) ].	Decrease ciprofloxacin tablets absorption, resulting in lower serum and urine levels.
Probenecid	Use with caution (Interferes with renal tubular secretion of ciprofloxacin tablets and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin tablets toxicity may occur.

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Table 14: Clinically Important Drug Interactions: Effect of other Drugs on Guanfacine Extended-Release
Concomitant Drug Name or Drug Class	Clinical Rationale and Magnitude of Drug Interaction	Clinical Recommendation
Strong and moderate CYP3A4 inhibitors, e.g., ketoconazole, fluconazole	Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in an increase in exposure	Consider dose reduction [see Dosage and administration ( 2.7 )]
Strong and moderate CYP3A4 inducers, e.g., rifampin, efavirenz	Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in a decrease in exposure	Consider dose increase [see Dosage and administration ( 2.7 )]

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Specific Drugs Reported
also: diet high in vitamin K unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported.
alcohol† aminoglutethimide amobarbital atorvastatin† azathioprine butabarbital butalbital carbamazepine chloral hydrate† chlordiazepoxide chlorthalidone	cholestyramine† clozapine corticotropin cortisone cyclophosphamide† dicloxacillin ethchlorvynol glutethimide griseofulvin haloperidol meprobamate	6-mercaptopurine methimazole† moricizine hydrochloride† nafcillin paraldehyde pentobarbital phenobarbital phenytoin† pravastatin† prednisone† primidone	propylthiouracil† raloxifene ranitidine† rifampin secobarbital spironolactone sucralfate trazodone vitamin C (high dose) vitamin K warfarin underdosage

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Drugs That Interfere with Hemostasis
Clinical Impact:	Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of celecoxib capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions (5.11) ].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions (5.2) ]. In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200-400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100-325 mg).
Intervention:	Concomitant use of celecoxib capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions (5.11) ]. Celecoxib capsules is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of celecoxib capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of celecoxib capsules and ACE-inhibitors or ARBs in patients who are elderly, volume- depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions (5.6) ]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of celecoxib capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see Warnings and Precautions (5.6) ].
Digoxin
Clinical Impact:	The concomitant use of celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of celecoxib capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of celecoxib capsules and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Celecoxib capsules have no effect on methotrexate pharmacokinetics.
Intervention:	During concomitant use of celecoxib capsules and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of celecoxib capsules and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of celecoxib capsules and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions (5.2) ].
Intervention:	The concomitant use of celecoxib with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of celecoxib capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of celecoxib capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or inducers
Clinical Impact:	Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib.
Intervention	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [ see Clinical Pharmacology (12.3) ].
CYP2D6 substrates
Clinical Impact:	In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs.
Intervention	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [ see Clinical Pharmacology (12.3) ].
Corticosteroids
Clinical Impact:	Concomitant use of corticosteroids with celecoxib capsules may increase the risk of GI ulceration or bleeding.
Intervention	Monitor patients with concomitant use of celecoxib capsules with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)].

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Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio Change relative to reference)		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	Cmax	Risperidone Dose Recommendation
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug Name	Effect on Concentration of Lopinavir or Concomitant Drug	Clinical Comments
HIV-1 Antiviral Agents
HIV-1 Protease Inhibitor: fosamprenavir/ritonavir	↓ amprenavir ↓ lopinavir	An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: indinavir*	↑ indinavir	Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor: nelfinavir*	↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir	KALETRA once daily in combination with nelfinavir is not recommended [see Dosage and Administration ( 2)] .
HIV-1 Protease Inhibitor: ritonavir*	↑ lopinavir	Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: saquinavir	↑ saquinavir	The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor: tipranavir*	↓ lopinavir	Co-administration with tipranavir (500 mg twice daily) and ritonavir (200 mg twice daily) is not recommended.
HIV CCR5 – Antagonist: maraviroc*	↑ maraviroc	When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for maraviroc.
Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz, nevirapine	↓ lopinavir	Increase the dose of KALETRA tablets to 500/125 mg when KALETRA tablet is co-administered with efavirenz or nevirapine. KALETRA once daily in combination with efavirenz or nevirapine is not recommended [see Dosage and Administration ( 2)] .
Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine	↑ lopinavir	Appropriate doses of the combination with respect to safety and efficacy have not been established.
Nucleoside Reverse Transcriptase Inhibitor: didanosine		KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).
Nucleoside Reverse Transcriptase Inhibitor: tenofovir disoproxil fumarate*	↑ tenofovir	Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitors: abacavir zidovudine	↓ abacavir ↓ zidovudine	The clinical significance of this potential interaction is unknown.
Other Agents
Antiarrhythmics e.g. amiodarone, bepridil, lidocaine (systemic), quinidine	↑ antiarrhythmics	For contraindicated antiarrhythmics, [see Contraindications ( 4)] . Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.
Anticancer Agents: vincristine, vinblastine, dasatinib, nilotinib	↑ anticancer agents	For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.
Anticoagulants: warfarin, rivaroxaban	↑↓ warfarin ↑ rivaroxaban	Concentrations of warfarin may be affected. Initial frequent monitoring of the INR during KALETRA and warfarin co-administration is recommended. Avoid concomitant use of rivaroxaban and KALETRA. Co-administration of KALETRA and rivaroxaban may lead to increased risk of bleeding.
Anticonvulsants: carbamazepine, phenobarbital, phenytoin	↓ lopinavir ↓ phenytoin	KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA once daily in combination with carbamazepine, phenobarbital, or phenytoin is not recommended. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
Anticonvulsants: lamotrigine, valproate	↓ lamotrigine ↓ or ↔ valproate	A dose increase of lamotrigine or valproate may be needed when co-administered with KALETRA and therapeutic concentration monitoring for lamotrigine may be indicated; particularly during dosage adjustments.
Antidepressant: bupropion	↓ bupropion ↓ active metabolite, hydroxybupropion	Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant: trazodone	↑ trazodone	Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. A lower dose of trazodone should be considered.
Anti-infective: clarithromycin	↑ clarithromycin	For patients with renal impairment, adjust clarithromycin dose as follows: For patients on KALETRA with CL _CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients on KALETRA with CL _CR < 30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary.
Antifungals: ketoconazole, itraconazole, voriconazole isavuconazonium sulfate	↑ ketoconazole ↑ itraconazole ↓ voriconazole ↑ isavuconazonium	High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended. The coadministration of voriconazole and KALETRA should be avoided unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Isavuconazonium and Kaletra should be coadministered with caution. Alternative antifungal therapies should be considered in these patients.
Anti-gout: colchicine	↑ colchicine	Concomitant administration with colchicine is contraindicated in patients with renal and/or hepatic impairment [see Contraindications ( 4)] . For patients with normal renal or hepatic function: Treatment of gout flares-co-administration of colchicine in patients on KALETRA: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on KALETRA: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial: bedaquiline	↑ bedaquiline	For contraindicated antimycobacterials, [see Contraindications ( 4)] . Bedaquiline should only be used with KALETRA if the benefit of co-administration outweighs the risk.
Antimycobacterial: rifabutin*	↑ rifabutin and rifabutin metabolite	Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antiparasitic: atovaquone	↓ atovaquone	Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Antipsychotics: quetiapine	↑ quetiapine	Initiation of KALETRA in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking KALETRA: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
Sedative/hypnotics: parenterally administered midazolam	↑ midazolam	For contraindicated sedative/hypnotics, [see Contraindications ( 4)] . If KALETRA is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Contraceptive: ethinyl estradiol*	↓ ethinyl estradiol	Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.
Corticosteroids (systemic): e.g. budesonide, dexamethasone, prednisone	↓ lopinavir ↑ glucocorticoids	Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly. Concomitant use of glucocorticoids that are metabolized by CYP3A, particularly for long-term use, should consider the potential benefit of treatment versus the risk of systemic corticosteroid effects. Concomitant use may increase the risk for development of systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression.
Dihydropyridine Calcium Channel Blockers: e.g. felodipine, nifedipine, nicardipine	↑ dihydropyridine calcium channel blockers	Clinical monitoring of patients is recommended and a dose reduction of the dihydropyridine calcium channel blocker may be considered.
Disulfiram/metronidazole		KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Endothelin Receptor Antagonists: bosentan	↑ bosentan	Co-administration of bosentan in patients on KALETRA: In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Co-administration of KALETRA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA. After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Hepatitis C direct acting antivirals: boceprevir* simeprevir ombitasvir/parataprevir/ ritonavir and dasabuvir*	↓ lopinavir ↓ boceprevir ↓ ritonavir ↑simeprevir ↑ ombitsavir ↑ parataprevir ↑ ritonavir ↔ dasabuvir	For contraindicated hepatitis C direct acting antivirals, [see Contraindications ( 4)] . It is not recommended to co-administer KALETRA and boceprevir, simeprevir, or ombitasvir/parataprevir/ritonavir and dasabuvir.
HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin	↑ atorvastatin ↑ rosuvastatin	For contraindicated HMG-CoA reductase inhibitors, [see Contraindications ( 4)] . Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day.
Immunosuppressants: e.g. cyclosporine, tacrolimus, sirolimus	↑ immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Inhaled or Intranasal Steroids e.g.: fluticasone, budesonide	↑ glucocorticoids	Concomitant use of KALETRA and fluticasone or other glucocorticoids that are metabolized by CYP3A is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. Concomitant use may result in increased steroid concentrations and reduce serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during postmarketing use in patients when certain ritonavir-containing products have been co-administered with fluticasone propionate or budesonide.
Long-acting beta-adrenoceptor Agonist: salmeterol	↑ salmeterol	Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesics: methadone,* fentanyl	↓ methadone ↑ fentanyl	Dosage of methadone may need to be increased when co-administered with KALETRA. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA.
PDE5 inhibitors: avanafil, sildenafil, tadalafil, vardenafil	↑ avanafil ↑ sildenafil ↑ tadalafil ↑ vardenafil	For contraindicated PDE5 inhibitors, [see Contraindications ( 4)] . Do not use KALETRA with avanafil because a safe and effective avanafil dosage regimen has not been established. Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio ^®) is contraindicated [see Contraindications ( 4)] . The following dose adjustments are recommended for use of tadalafil (Adcirca ^®) with KALETRA: Co-administration of ADCIRCA in patients on KALETRA: In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Co-administration of KALETRA in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: It is recommended not to exceed the following doses: • Sildenafil: 25 mg every 48 hours • Tadalafil: 10 mg every 72 hours • Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events.
* see Clinical Pharmacology ( 12.3) for magnitude of interaction.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

Table name:

Drug		Effect
Phenylephrine with prior administration of monoamine oxidase inhibitors (MAOI).		Cardiac pressor response potentiated. May cause acute hypertensive crisis.
Phenylephrine with tricyclic anti-depressants.		Pressor response increased.
Phenylephrine with ergot alkaloids.		Excessive rise in blood pressure.
Phenylephrine with bronchodilator sympathomimetic agents and with epinephrine or other sympathomimetics.		Tachycardia or other arrhythmias may occur.
Phenylephrine with prior administration of propranolol or other β-adrenergic blockers.		Cardiostimulating effects blocked.
Phenylephrine with atropine sulfate.		Reflex bradycardia blocked; pressor response enhanced.
Phenylephrine with prior administration of phentolamine or other α-adrenergic blockers.		Pressor response decreased.
Phenylephrine with diet preparations, such as amphetamines or phenylpropanolamine.		Synergistic adrenergic response.

Table name:

Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C Protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

Table name:

Table 1: Drugs that may have their plasma concentrations increased by itraconazole
Drug Class	Contraindicated	Not Recommended	Use with Caution	Comments
	Under no circumstances is the drug to be coadministered with itraconazole, and up to two weeks after discontinuation of treatment with itraconazole.	It is recommended that the use of the drug be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If coadministration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of the interacting drug is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured. The label of the coadministered drug should be consulted for information on dose adjustment and adverse effects.	Careful monitoring is recommended when the drug is coadministered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of the interacting drug, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured. The label of the coadministered drug should be consulted for information on dose adjustment and adverse effects.
Alpha Blockers		tamsulosin
Analgesics	methadone		alfentanil, buprenorphine IV and sublingual, fentanyl, oxycodone, sufentanil	Methadone: The potential increase in plasma concentrations of methadone when coadministered with Itraconazole Capsules may increase the risk of serious cardiovascular events including QTc prolongation and torsade de pointes. Fentanyl: The potential increase in plasma concentrations of fentanyl when coadministered with Itraconazole Capsules may increase the risk of potentially fatal respiratory depression. Sufentanil: No human pharmacokinetic data of an interaction with itraconazole are available. In vitro data suggest that sufentanil is metabolized by CYP3A4 and so potentially increased sufentanil plasma concentrations would be expected when coadministered with Itraconazole Capsules.
Antiarrhythmics	disopyramide, dofetilide, dronedarone, quinidine		digoxin	Disopyramide, dofetilide, dronedarone, quinidine: The potential increase in plasma concentrations of these drugs when coadministered with Itraconazole Capsules may increase the risk of serious cardiovascular events including QTc prolongation.
Antibacterials	telithromycin, in subjects with severe renal impairment or severe hepatic impairment	rifabutin	telithromycin	Telithromycin: The potential increase in plasma concentrations of telithromycin in subjects with severe renal impairment or severe hepatic impairment, when coadministered with Itraconazole Capsulesmay increase the risk of serious cardiovascular events including QT prolongation and torsade de pointes. Rifabutin: See also under ‘Drugs that may decrease itraconazole plasma concentrations’
Anticoagulants and Antiplatelet Drugs	ticagrelor	apixaban, rivaroxaban	coumarins, cilostazol, dabigatran	Ticagrelor: The potential increase in plasma concentrations of ticagrelor may increase the risk of bleeding. Coumarins: Itraconazole Capsules may enhance the anticoagulant effect of coumarin-like drugs, such as warfarin.
Anticonvulsants		carbamazepine		Carbamazepine: In vivo studies have demonstrated an increase in plasma carbamazepine concentrations in subjects concomitantly receiving ketoconazole. Although there are no data regarding the effect of itraconazole on carbamazepine metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of Itraconazole Capsules and carbamazepine may inhibit the metabolism of carbamazepine.See also under ‘Drugs that may decrease itraconazole plasma concentrations’.
Antidiabetics			repaglinide,saxagliptin
Antihelmintics and Antiprotozoals			praziquantel
Antimigraine Drugs	ergot alkaloids, such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine)		eletriptan	Ergot Alkaloids: The potential increase in plasma concentrations of ergot alkaloids when coadministered with Itraconazole Capsules may increase the risk of ergotism, ie. a risk for vasospasm potentially leading to cerebral ischemia and/or ischemia of the extremities.
Antineoplastics	irinotecan	axitinib, dabrafenib, dasatinib, ibrutinib, nilotinib, sunitinib,trabectedin	bortezomib, busulphan, docetaxel, erlotinib, gefitinib, imatinib, ixabepilone, lapatinib, ponatinib, trimetrexate, vinca alkaloids	Irinotecan: The potential increase in plasma concentrations of irinotecan when coadministered with Itraconazole Capsules may increase the risk of potentially fatal adverse events.
Antipsychotics, Anxiolytics and Hypnotics	lurasidone, oral midazolam, pimozide, triazolam		alprazolam,aripiprazole,buspirone,diazepam,haloperidol,midazolam IV,perospirone,quetiapine,ramelteon,risperidone	Midazolam, triazolam:Coadministration of Itraconazole Capsules and oral midazolam, or triazolam may cause several-fold increases in plasma concentrations of these drugs. This may potentiate and prolong hypnotic and sedative effects, especially with repeated dosing or chronic administration of these agents. Pimozide: The potential increase in plasma concentrations of pimozide when coadministered with Itraconazole Capsules may increase the risk of serious cardiovascular events including QTc prolongation and torsade de pointes.
Antivirals		simeprevir	maraviroc,indinavir,ritonavir,saquinavir	Indinavir, ritonavir: See also under ‘Drugs that may increase itraconazole plasma concentrations’.
Beta Blockers			nadolol
Calcium Channel Blockers	felodipine,nisoldipine		other dihydropyridines,verapamil	Calcium channel blockers can have a negative inotropic effect which may be additive to those of itraconazole. The potential increase in plasma concentrations of calcium channel blockers when co-administered with Itraconazole Capsules may increase the risk of congestive heart failure. Dihydropyridines: Concomitant administration of Itraconazole Capsules may cause several-fold increases in plasma concentrations of dihydropyridines. Edema has been reported in patients concomitantly receiving Itraconazole Capsules and dihydropyridine calcium channel blockers.
Cardiovascular Drugs, Miscellaneous	Ivabradine, ranolazine	aliskiren, sildenafil, for the treatment of pulmonary hypertension	bosentan, riociguat	Ivabradine: The potential increase in plasma concentrations of ivabradine when coadministered with Itraconazole Capsules may increase the risk of ivabradine-related adverse events, such as atrial fibrillation, bradycardia, sinus arrest and heart block. Ranolazine: The potential increase in plasma concentrations of ranolazine when coadministered with Itraconazole Capsules may increase the risk of serious cardiovascular events including QTc prolongation.
Diuretics	eplerenone			Eplerenone: The potential increase in plasma concentrations f eplerenone when coadministered with Itraconazole Capsules may increase the risk of hyperkalemia and hypotension.
Gastrointestinal Drugs	cisapride		aprepitant	Cisapride: The potential increase in plasma concentrations of cisapride when oadministered with Itraconazole Capsules may increase the risk of serious cardiovascular events including QTc prolongation.
Immunosuppressants		everolimus, temsirolimus	budesonide,ciclesonide,cyclosporine,dexamethasone,fluticasone,methylprednisolone,rapamycin (also known as sirolimus),tacrolimus
Lipid Regulating Drugs	lovastatin, simvastatin		atorvastatin	The potential increase in plasma concentrations of atorvastatin,lovastatin, and simvastatin when coadministered with Itraconazole Capsules may increase the risk of skeletal muscle toxicity,including rhabdomyolysis.
Respiratory Drugs		salmeterol
Urological Drugs	fesoterodine, in subjects with moderate to severe renal impairment, or moderate to severe hepatic impairment, solifenacin, in subjects with severe renal impairment or moderate to severe hepatic impairment	darifenacin, vardenafil	Fesoterodine, oxybutynin, sildenafil, for the treatment of erectile dysfunction, solifenacin, tadalafil, tolterodine	Fesoterodine: The potential increase in plasma concentrations of the fesoterodine active metabolite may be greater in subjects with moderate to severe renal impairment, or moderate to severe hepatic impairment, which may lead to an increased risk of adverse reactions. Solifenacin: The potential increase in plasma concentrations of solifenacin in subjects with severe renal impairment or moderate to severe hepatic impairment, when coadministered with Itraconazole Capsules may increase the risk of serious cardiovascular events including QT prolongation.
Other	colchicine, in subjects with renal or hepatic impairment	colchicines, conivaptan, tolvaptan	cinacalcet,	Colchicine: The potential increase in plasma concentrations of colchicine when coadministered with Itraconazole Capsules may increase the risk of potentially fatal adverse events. Conivaptan and Tolvaptan: A safe and effective dose of either conivaptan or tolvaptan has not been established when coadministered with Itraconazole Capsules.

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Table 3 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 4 for Magnitude of Interaction.
Drug Name	Effect on Concentration of Nevirapine or Concomitant Drug	Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir*	↓ Atazanavir ↑ Nevirapine	Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir* Fosamprenavir/Ritonavir*	↓ Amprenavir ↑ Nevirapine ↓ Amprenavir ↑ Nevirapine	Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir*	↓ Indinavir	The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir*	↓Lopinavir	Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir*	↓Nelfinavir M8 Metabolite ↓Nelfinavir C_min	The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/ritonavir	The interaction between Nevirapine and saquinavir/ritonavir has not been evaluated	The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz* Delavirdine Etravirine Rilpivirine	↓ Efavirenz	The appropriate doses of these combinations with respect to safety and efficacy have not been established. Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.
Other Agents
Analgesics: Methadone*	↓ Methadone	Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics: Amiodarone, disopyramide, lidocaine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Antibiotics: Clarithromycin* Rifabutin* Rifampin*	↓ Clarithromycin ↑ 14-OH clarithromycin ↑ Rifabutin ↓ Nevirapine	Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered. Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants: Carbamazepine, clonazepam, ethosuximide	Plasma concentrations of nevirapine and the anticonvulsant may be decreased.	Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals: Fluconazole* Ketoconazole* Itraconazole	↑Nevirapine ↓ Ketoconazole ↓ Itraconazole	Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events. Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics: Warfarin	Plasma concentrations may be increased.	Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers: Diltiazem, nifedipine, verapamil	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Cancer chemotherapy: Cyclophosphamide	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Ergot alkaloids: Ergotamine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Motility agents: Cisapride	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Opiate agonists: Fentanyl	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Oral contraceptives: Ethinyl estradiol and Norethindrone*	↓ Ethinyl estradiol ↓ Norethindrone	Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.
* The interaction between Nevirapine and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.

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Table 3Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin	Monitor phenytoin level (7)
Methotrexate	Monitor for methotrexate toxicity (7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased Ciprofloxacin Tablets, USP absorption. Take 2 hours before or 6 hours after Ciprofloxacin Tablets, USP (7)

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Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)	VIAGRA 100 mg
Supine	7.9 (4.6, 11.1)
Standing	4.3 (-1.8,10.3)

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Digoxin concentrations increased greater than 50%
	Digoxin Serum Concentration Increase	Digoxin AUC Increase	Recommendations
Quinidine	NA	54-83%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
Ritonavir	NA	86%
Digoxin concentrations increased less than 50%
Amiodarone	17%	40%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
Propafenone	28%	29%
Quinine	NA	34-38%
Spironolactone	NA	44%
Verapamil	NA	24%

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Specific Drugs Reported
also: diet high in vitamin K unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported.
alcohol† aminoglutethimide amobarbital atorvastatin† azathioprine butabarbital butalbital carbamazepine chloral hydrate† chlordiazepoxide chlorthalidone	cholestyramine† clozapine corticotropin cortisone cyclophosphamide† dicloxacillin ethchlorvynol glutethimide griseofulvin haloperidol meprobamate	6-mercaptopurine methimazole† moricizine hydrochloride† nafcillin paraldehyde pentobarbital phenobarbital phenytoin† pravastatin† prednisone† primidone	propylthiouracil† raloxifene ranitidine† rifampin secobarbital spironolactone sucralfate trazodone vitamin C (high dose) vitamin K warfarin underdosage

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Factors	Dosage Adjustments for Aripiprazole
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors	Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double usual dose over 1 to 2 weeks

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Calcium Channel Blockers	Antifungals	Antibiotics	Glucocorticoids	Other Drugs
diltiazem	fluconazole	azithromycin	methylprednisolone	allopurinol
nicardipine	itraconazole	clarithromycin		amiodarone
verapamil	ketoconazole	erythromycin		bromocriptine
	voriconazole	quinupristin/dalfopristin		colchicine
				danazol
				imatinib
				metoclopramide
				nefazodone
				oral contraceptives

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Calcium Channel Blockers	Antifungals	Antibiotics	Glucocorticoids	Other Drugs
diltiazem	fluconazole	azithromycin	methylprednisolone	allopurinol
nicardipine	itraconazole	clarithromycin		amiodarone
verapamil	ketoconazole	erythromycin		bromocriptine
		quinupristin/		colchicine
	voriconazole	dalfopristin		danazol
				imatinib
				metoclopramide
				nefazodone
				oral contraceptives

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Table 2: Clinically Significant Drug Interactions with Oxaprozin Drugs That Interfere with Hemostasis
Clinical Impact:	Oxaprozin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of oxaprozin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of oxaprozin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11 )].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention:	Concomitant use of oxaprozin and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Oxaprozin is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of oxaprozin and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of oxaprozin and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of oxaprozin with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact:	The concomitant use of oxaprozin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of oxaprozin and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of oxaprozin and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction) because NSAID administration may result in increased plasma levels of methotrexate, especially in patients receiving high doses of methotrexate.
Intervention:	During concomitant use of oxaprozin and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of oxaprozin and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of oxaprozin and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of oxaprozin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention:	The concomitant use of oxaprozin with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of oxaprozin and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of oxaprozin and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Corticosteroids
Clinical Impact:	Concomitant use of corticosteroids with oxaprozin may increase the risk of GI ulceration or bleeding.
Intervention:	Monitor patients with concomitant use of oxaprozin with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)].
Glyburide
Clinical Impact:	While oxaprozin does alter the pharmacokinetics of glyburide, coadministration of oxaprozin to type II non-insulin dependent diabetic patients did not affect the area under the glucose concentration curve nor the magnitude or duration of control.
Intervention:	During concomitant use of oxaprozin and glyburide, monitor patient’s blood glucose in the beginning phase of cotherapy.

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Table II. Clinically significant drug interactions with theophylline^*.
^* Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
^** Average effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Drug	Type of Interaction	Effect^**
Adenosine	Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.
Alcohol	A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours.	30% increase
Allopurinol	Decreases theophylline clearance at allopurinol doses ≥ 600 mg/day.	25% increase
Aminoglutethimide	Increases theophylline clearance by induction of microsomal enzyme activity.	25% decrease
Carbamazepine	Similar to aminoglutethimide.	30% decrease
Cimetidine	Decreases theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase
Ciprofloxacin	Similar to cimetidine.	40% increase
Clarithromycin	Similar to erythromycin.	25% increase
Diazepam	Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant while theophylline blocks adenosine receptors.	Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram	Decreases theophylline clearance by inhibiting hydroxylation and demethylation.	50% increase
Enoxacin	Similar to cimetidine.	300% increase
Ephedrine	Synergistic CNS effects	Increased frequency of nausea, nervousness, and insomnia.
Erythromycin	Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.	35% increase Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen	Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.	30% increase
Flurazepam	Similar to diazepam.	Similar to diazepam.
Fluvoxamine	Similar to cimetidine	Similar to cimetidine
Halothane	Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.	Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A	Decreases theophylline clearance.	100% increase
Isoproterenol (IV)	Increases theophylline clearance.	20% decrease
Ketamine	Pharmacologic	May lower theophylline seizure threshold.
Lithium	Theophylline increases renal lithium clearance.	Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam	Similar to diazepam.	Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance	20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine	Similar to disulfiram.	80% increase
Midazolam	Similar to diazepam.	Similar to diazepam.
Moricizine	Increases theophylline clearance.	25% decrease
Pancuronium	Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.	Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline	Decreases theophylline clearance.	30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.	25% decrease after two weeks of concurrent PB.
Phenytoin	Phenytoin increases theophylline clearance by increasing microsomal enzyme activity.	Serum theophylline and phenytoin concentrations decrease about 40%.
	Theophylline decreases phenytoin absorption.
Propafenone	Decreases theophylline clearance and pharmacologic interaction.	40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and pharmacologic interaction.	100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin	Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.	20-40% decrease
Sulfinpyrazone	Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.	20% decrease
Tacrine	Similar to cimetidine, also increases renal clearance of theophylline.	90% increase
Thiabendazole	Decreases theophylline clearance.	190% increase
Ticlopidine	Decreases theophylline clearance.	60% increase
Troleandomycin	Similar to erythromycin.	33-100% increase depending on troleandomycin dose.
Verapamil	Similar to disulfiram.	20% increase

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Table 13. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Bleeding times
Clinical Impact:	Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention:	This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact:	The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention:	Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact:	Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention:	This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.

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Table 2: Clinically Significant Drug Interactions with CONZIP
Inhibitors of CYP2D6
Clinical Impact:	The concomitant use of CONZIP and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1, particularly when an inhibitor is added after a stable dose of CONZIP is achieved. Since M1 is a more potent μ-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease and the M1 plasma concentration will increase which could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, and may cause potentially fatal respiratory depression [see Clinical Pharmacology (12.3)].
Intervention:	If concomitant use of a CYP2D6 inhibitor is necessary, follow patients closely for adverse reactions including opioid withdrawal, seizures, and serotonin syndrome. If a CYP2D6 inhibitor is discontinued, consider lowering CONZIP dosage until stable drug effects are achieved. Follow patients closely for adverse events including respiratory depression and sedation.
Examples	Quinidine, fluoxetine, paroxetine and bupropion
Inhibitors of CYP3A4
Clinical Impact:	The concomitant use of CONZIP and CYP3A4 inhibitors can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1. Follow patients closely for increased risk of serious adverse events including seizures and serotonin syndrome, and adverse reactions related to opioid toxicity including potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of CONZIP is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy and possibly signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol.
Intervention:	If concomitant use is necessary, consider dosage reduction of CONZIP until stable drug effects are achieved. Follow patients closely for seizures and serotonin syndrome, and signs of respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the CONZIP dosage until stable drug effects are achieved and follow patients for signs and symptoms of opioid withdrawal.
Examples	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact:	The concomitant use of CONZIP and CYP3A4 inducers can decrease the plasma concentration of tramadol, [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol, [see Warnings and Precautions (5.4)]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause seizures and serotonin syndrome, and potentially fatal respiratory depression .
Intervention:	If concomitant use is necessary, consider increasing the CONZIP dosage until stable drug effects are achieved. Follow patients for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider CONZIP dosage reduction and monitor for seizures and serotonin syndrome, and signs of sedation and respiratory depression. Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of CONZIP and carbamazepine is not recommended.
Examples:	Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.5)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, , antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue CONZIP if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.7)] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
Intervention:	Do not use CONZIP in patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of CONZIP and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Tramadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of CONZIP and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when CONZIP is used concomitantly with anticholinergic drugs.
Digoxin
Clinical Impact:	Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity.
Intervention:	Follow patients for signs of digoxin toxicity and adjust dosage of digoxin as needed.
Warfarin
Clinical Impact:	Post-marketing surveillance of tramadol has revealed rare reports of alteration of warfarin effect, including elevation of prothrombin times.
Intervention:	Monitor the prothrombin time of patients on warfarin for signs of an interaction and adjust the dosage of warfarin as needed.

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Figure 1: Effect of interacting drugs on the pharmacokinetics of venlafaxine and active metabolite O-desmethylvenlafaxine (ODV).

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^a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. ^b = Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. NE = Not Evaluated
AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Table 2: Clinically Significant Drug Interactions with mefenamic acid
Drugs That Interfere with Hemostasis
Clinical Impact:	Mefenamic acid and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of mefenamic acid and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of mefenamic acid with anticoagulants (e.g.,warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity ).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation ).
Intervention:	Concomitant use of mefenamic acid and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity ). Mefenamic acid is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of mefenamic acid and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of mefenamic acid and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia ). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of mefenamic acid with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia ).
Digoxin
Clinical Impact:	The concomitant use of mefenamic acid with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of mefenamic acid and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of mefenamic acid and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of mefenamic acid and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of mefenamic acid and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention:	During concomitant use of mefenamic acid and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of mefenamic acid with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation ).
Intervention:	The concomitant use of mefenamic acid with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of mefenamic acid and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of mefenamic acid and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacid
Clinical Impact:	In a single dose study (n=6), ingestion of an antacid containing 1.7-gram of magnesium hydroxide with 500-mg of mefenamic acid increased the C_max and AUC of mefenamic acid by 125% and 36%, respectively.
Intervention:	Concomitant use of mefenamic acid and antacids is not generally recommended because of possible increased adverse events.

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Antibiotics	Antineoplastics	Antifungals	Anti-inflammatory Drugs	Gastrointestinal Agents	Immunosuppressives	Other Drugs
ciprofloxacin	melphalan	amphotericin B	azapropazon	cimetidine	tacrolimus	fibric acid derivatives (e.g., bezafibrate, fenofibrate)
gentamicin		ketoconazole	colchicine	ranitidine		methotrexate
tobramycin			diclofenac
vancomycin			naproxen
trimethoprim with sulfamethoxazole			sulindac

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Table 4: Clinically Relevant Interactions Affecting Omeprazole When Co-Administered with Other Drugs
CYP2C19 or CYP3A4 Inducers
Clinical Impact:	Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention:	St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions (5.9)]. Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:	Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
Intervention:	Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole.

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Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)	VIAGRA 50 mg (95% CI)
Supine	9.08 (5.48, 12.68)
Standing	11.62 (7.34, 15.90)

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AED Co - administered	AED Concentration	Topiramate Concentration
Phenytoin	NCor25%increase ^a	48%decrease
Carbamazepine(CBZ)	NC	40%decrease
CBZepoxide ^b	NC	NE
Valproic acid	11%decrease	14%decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NCatTPM dosesupto400 mg/day	13%decrease

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Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Drugs that Affect Renal Function	A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics	Dofetilide	Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
	Sotalol	Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
	Dronedarone	Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog	Teriparatide	Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement	Thyroid	Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics	Epinephrine Norepinephrine Dopamine	Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents	Succinylcholine	May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements	Calcium	If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers		Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.

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Strong CYP3A4 Inhibitors
Clinical Impact:	Concomitant use of REXULTI with strong CYP3A4 inhibitors increased the exposure of brexpiprazole compared to the use of REXULTI alone [see Clinical Pharmacology (12.3)]
Intervention:	With concomitant use of REXULTI with a strong CYP3A4 inhibitor, reduce the REXULTI dosage [see Dosage and Administration (2.5)]
Examples:	itraconazole, clarithromycin, ketoconazole
Strong CYP2D6 Inhibitors*
Clinical Impact:	Concomitant use of REXULTI with strong CYP2D6 inhibitors increased the exposure of brexpiprazole compared to the use of REXULTI alone [see Clinical Pharmacology (12.3)]
Intervention:	With concomitant use of REXULTI with a strong CYP2D6 inhibitor, reduce the REXULTI dosage [see Dosage and Administration (2.5)]
Examples:	paroxetine, fluoxetine, quinidine
Both CYP3A4 Inhibitors and CYP2D6 Inhibitors
Clinical Impact:	Concomitant use of REXULTI with 1) a strong CYP3A4 inhibitor and a strong CYP2D6 inhibitor; or 2) a moderate CYP3A4 inhibitor and a strong CYP2D6 inhibitor; or 3) a strong CYP3A4 inhibitor and a moderate CYP2D6 inhibitor; or 4) a moderate CYP3A4 inhibitor and a moderate CYP2D6 inhibitor, increased the exposure of brexpiprazole compared to the use of REXULTI alone [see Clinical Pharmacology (12.3)]
Intervention:	With concomitant use of REXULTI with 1) a strong CYP3A4 inhibitor and a strong CYP2D6 inhibitor; or 2) a moderate CYP3A4 inhibitor and a strong CYP2D6 inhibitor; or 3) a strong CYP3A4 inhibitor and a moderate CYP2D6 inhibitor; or 4) a moderate CYP3A4 inhibitor and a moderate CYP2D6 inhibitor, decrease the REXULTI dosage [see Dosage and Administration (2.5)]
Examples:	1) itraconazole + quinidine 2) fluconazole + paroxetine 3) itraconazole + duloxetine 4) fluconazole + duloxetine
Strong CYP3A4 Inducers
Clinical Impact:	Concomitant use of REXULTI and a strong CYP3A4 inducer decreased the exposure of brexpiprazole compared to the use of REXULTI alone [see Clinical Pharmacology (12.3)]
Intervention:	With concomitant use of REXULTI with a strong CYP3A4 inducer, increase the REXULTI dosage [see Dosage and Administration (2.5)]
Examples:	rifampin, St. John’s wort

Table 7. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug Name	Effect on Concentration of Amprenavir or Concomitant Drug	Clinical Comment
HCV/HIV-Antiviral Agents
HCV protease inhibitor: Boceprevir	LEXIVA: ↓Amprenavir (predicted) ↔ or ↓Boceprevir (predicted) LEXIVA/ritonavir: ↓Amprenavir (predicted) ↓Boceprevir (predicted)	Coadministration of LEXIVA or LEXIVA/ritonavir and boceprevir is not recommended.
HCV protease inhibitor: Simeprevir	LEXIVA: ↔Amprenavir (predicted) ↑ or ↓Simeprevir (predicted) LEXIVA/ritonavir: ↔Amprenavir (predicted) ↑Simeprevir (predicted)	Coadministration of LEXIVA or LEXIVA/ritonavir and simeprevir is not recommended.
HCV protease inhibitor: Paritaprevir (coformulated with ritonavir and ombitasvir and coadministered with dasabuvir)	LEXIVA: ↑Amprenavir (predicted) ↑ or ↔Paritaprevir (predicted) LEXIVA/ritonavir: ↑ or ↔Amprenavir (predicted) ↑Paritaprevir (predicted)	Appropriate doses of the combinations with respect to safety and efficacy have not been established. LEXIVA 1400 mg once daily may be considered when coadministered with paritaprevir/ritonavir/ombitasvir/ dasabuvir. Coadministration of LEXIVA/ritonavir and paritaprevir/ritonavir/ombitasvir/ dasabuvir is not recommended.
Non-nucleoside reverse transcriptase inhibitor: Efavirenz^a	LEXIVA: ↓Amprenavir LEXIVA/ritonavir: ↓Amprenavir	Appropriate doses of the combinations with respect to safety and efficacy have not been established. An additional 100 mg/day (300 mg total) of ritonavir is recommended when efavirenz is administered with LEXIVA/ritonavir once daily. No change in the ritonavir dose is required when efavirenz is administered with LEXIVA plus ritonavir twice daily.
Non-nucleoside reverse transcriptase inhibitor: Nevirapine^a	LEXIVA: ↓Amprenavir ↑Nevirapine LEXIVA/ritonavir: ↓Amprenavir ↑Nevirapine	Coadministration of nevirapine and LEXIVA without ritonavir is not recommended. No dosage adjustment required when nevirapine is administered with LEXIVA/ritonavir twice daily. The combination of nevirapine administered with LEXIVA/ritonavir once-daily regimen has not been studied.
HIV protease inhibitor: Atazanavir^a	LEXIVA: Interaction has not been evaluated. LEXIVA/ritonavir: ↓Atazanavir ↔Amprenavir	Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitors: Indinavir^a, nelfinavir^a	LEXIVA: ↑Amprenavir Effect on indinavir and nelfinavir is not well established. LEXIVA/ritonavir: Interaction has not been evaluated.	Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitors: Lopinavir/ritonavir^a	↓Amprenavir ↓Lopinavir	An increased rate of adverse events has been observed. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitor: Saquinavir^a	LEXIVA: ↓Amprenavir Effect on saquinavir is not well established. LEXIVA/ritonavir: Interaction has not been evaluated.	Appropriate doses of the combination with respect to safety and efficacy have not been established.
HIV integrase inhibitor: Raltegravir^a	LEXIVA: ↓Amprenavir ↓Raltegravir LEXIVA/ritonavir: ↓Amprenavir ↓Raltegravir	Appropriate doses of the combination with respect to safety and efficacy have not been established.
HIV integrase inhibitor: Dolutegravir^a	LEXIVA/ritonavir: ↓Dolutegravir	The recommended dose of dolutegravir is 50 mg twice daily when coadministered with LEXIVA/ritonavir. Use an alternative combination where possible in patients with known or suspected integrase inhibitor resistance.
HIV CCR5 co-receptor antagonist: Maraviroc^a	LEXIVA/ritonavir: ↓Amprenavir ↑Maraviroc	No dosage adjustment required for LEXIVA/ritonavir. The recommended dose of maraviroc is 150 mg twice daily when coadministered with LEXIVA/ritonavir. LEXIVA should be given with ritonavir when coadministered with maraviroc.
Other Agents
Antiarrhythmics: Amiodarone, lidocaine (systemic), and quinidine	↑Antiarrhythmics	Use with caution. Increased exposure may be associated with life-threatening reactions such as cardiac arrhythmias. Therapeutic concentration monitoring, if available, is recommended for antiarrhythmics.
Anticoagulant: Warfarin		Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: Carbamazepine, phenobarbital, phenytoin Phenytoin^a	LEXIVA: ↓Amprenavir LEXIVA/ritonavir: ↑Amprenavir ↓Phenytoin	Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations in patients taking these agents concomitantly. Plasma phenytoin concentrations should be monitored and phenytoin dose should be increased as appropriate. No change in LEXIVA/ritonavir dose is recommended.
Antidepressant: Paroxetine, trazodone	↓Paroxetine ↑Trazodone	Any paroxetine dose adjustment should be guided by clinical effect (tolerability and efficacy). Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as LEXIVA, the combination should be used with caution and a lower dose of trazodone should be considered.
Antifungals: Ketoconazole^a, itraconazole	↑Ketoconazole ↑Itraconazole	Increase monitoring for adverse events. LEXIVA: Dose reduction of ketoconazole or itraconazole may be needed for patients receiving more than 400 mg ketoconazole or itraconazole per day. LEXIVA/ritonavir: High doses of ketoconazole or itraconazole (greater than 200 mg/day) are not recommended.
Anti-gout: Colchicine	↑Colchicine	Patients with renal or hepatic impairment should not be given colchicine with LEXIVA/ritonavir. LEXIVA/ritonavir and coadministration of colchicine: Treatment of gout flares: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). LEXIVA and coadministration of colchicine: Treatment of gout flares: 1.2 mg (2 tablets) x 1 dose. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg twice a day or 0.6 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once a day. Treatment of FMF: Maximum daily dose of 1.2 mg (may be given as 0.6 mg twice a day).
Antimycobacterial: Rifabutin^a	↑Rifabutin and rifabutin metabolite	A complete blood count should be performed weekly and as clinically indicated to monitor for neutropenia. LEXIVA: A dosage reduction of rifabutin by at least half the recommended dose is required. LEXIVA/ritonavir: Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (a maximum dose of 150 mg every other day or 3 times per week).
Antipsychotics: Quetiapine	LEXIVA/ritonavir: ↑Quetiapine	Initiation of LEXIVA with ritonavir in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine drug exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking LEXIVA with ritonavir: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
Lurasidone	↑Lurasidone	LEXIVA: If coadministration is necessary, reduce the lurasidone dose. Refer to the lurasidone prescribing information for concomitant use with moderate CYP3A4 inhibitors. LEXIVA/ritonavir: Use of lurasidone is contraindicated.
Benzodiazepines: Alprazolam, clorazepate, diazepam, flurazepam	↑Benzodiazepines	Clinical significance is unknown. A decrease in benzodiazepine dose may be needed.
Calcium channel blockers: Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine	↑Calcium channel blockers	Use with caution. Clinical monitoring of patients is recommended.
Corticosteroid: Dexamethasone	↓Amprenavir	Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations.
Endothelin-receptor antagonists: Bosentan	↑Bosentan	Coadministration of bosentan in patients on LEXIVA: In patients who have been receiving LEXIVA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Coadministration of LEXIVA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of LEXIVA. After at least 10 days following the initiation of LEXIVA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Histamine H₂-receptor antagonists: Cimetidine, famotidine, nizatidine, ranitidine^a	LEXIVA: ↓Amprenavir LEXIVA/ritonavir: Interaction not evaluated	Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations.
HMG-CoA reductase inhibitors: Atorvastatin^a	↑Atorvastatin	Titrate atorvastatin dose carefully and use the lowest necessary dose; do not exceed atorvastatin 20 mg/day.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus	↑Immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents.
Inhaled beta-agonist: Salmeterol	↑Salmeterol	Concurrent administration of salmeterol with LEXIVA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Inhaled/nasal steroid: Fluticasone	LEXIVA: ↑Fluticasone LEXIVA/ritonavir: ↑Fluticasone	Use with caution. Consider alternatives to fluticasone, particularly for long-term use. May result in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone. Coadministration of fluticasone and LEXIVA/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
Narcotic analgesic: Methadone	↓Methadone	Data suggest that the interaction is not clinically relevant; however, patients should be monitored for opiate withdrawal symptoms.
Oral contraceptives: Ethinyl estradiol/norethindrone^a	LEXIVA: ↓Amprenavir ↓Ethinyl estradiol LEXIVA/ritonavir: ↓Ethinyl estradiol	Alternative methods of non-hormonal contraception are recommended. May lead to loss of virologic response.^a Increased risk of transaminase elevations. No data are available on the use of LEXIVA/ritonavir with other hormonal therapies, such as hormone replacement therapy (HRT) for postmenopausal women.
PDE5 inhibitors: Sildenafil, tadalafil, vardenafil	↑Sildenafil ↑Tadalafil ↑Vardenafil	May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):
Proton pump inhibitors: Esomeprazole^a, lansoprazole, omeprazole, pantoprazole, rabeprazole	LEXIVA: ↔Amprenavir ↑Esomeprazole LEXIVA/ritonavir: ↔Amprenavir ↔Esomeprazole	Proton pump inhibitors can be administered at the same time as a dose of LEXIVA with no change in plasma amprenavir concentrations.
Tricyclic antidepressants: Amitriptyline, imipramine	↑Tricyclics	Therapeutic concentration monitoring is recommended for tricyclic antidepressants.

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Bleeding times
Clinical Impact:	Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention:	This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact:	The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention:	Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact:	Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention:	This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.

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Bleeding times
Clinical Impact:	Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention:	This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact:	The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention:	Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact:	Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention:	This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.

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DRUG	DESCRIPTION OF INTERACTION
Sulfonylureas	Hypoglycemia potentiated.
Methotrexate	Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants	Increased bleeding.

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Table 4 Other Potentially Significant Drug Interactions
Concomitant Drug Class or Food	Noted or Anticipated Outcome	Clinical Comment
HMG-Co A Reductase Inhibitors: atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin	Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality) P-gp substrate; rhabdomyolysis has been reported	Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy.
Other Lipid-Lowering Drugs: fibrates, gemfibrozil
Digitalis Glycosides: digoxin

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Table 3 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 4 for Magnitude of Interaction.
* The interaction between nevirapine and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.
Drug Name	Effect on Concentration of Nevirapine or Concomitant Drug	Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir*	↓ Atazanavir ↑ Nevirapine	Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir* Fosamprenavir/Ritonavir*	↓Amprenavir ↑Nevirapine ↓Amprenavir ↑Nevirapine	Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir*	↓ Indinavir	The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir*	↓ Lopinavir	Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir*	↓Nelfinavir M8 Metabolite ↓Nelfinavir Cmin	The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/ritonavir	The interaction between nevirapine and saquinavir/ritonavir has not been evaluated	The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz* Delavirdine Etravirine Rilpivirine	↓Efavirenz	The appropriate doses of these combinations with respect to safety and efficacy have not been established. Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.
Other Agents
Analgesics: Methadone*	↓Methadone	Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics: Amiodarone, disopyramide, lidocaine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Antibiotics: Clarithromycin* Rifabutin* Rifampin*	↓Clarithromycin ↑14-OH clarithromycin ↑Rifabutin ↓ Nevirapine	Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium aviumintracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered. Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants: Carbamazepine, clonazepam, ethosuximide	Plasma concentrations of nevirapine and the anticonvulsant may be decreased.	Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals: Fluconazole* Ketoconazole* Itraconazole	↑Nevirapine ↓ Ketoconazole ↓ Itraconazole	Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events. Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics: Warfarin	Plasma concentrations may be increased.	Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers: Diltiazem, nifedipine, verapamil	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Cancer chemotherapy: Cyclophosphamide	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Ergot alkaloids: Ergotamine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Motility agents: Cisapride	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Opiate agonists: Fentanyl	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Oral contraceptives: Ethinyl estradiol and Norethindrone*	↓ Ethinyl estradiol ↓ Norethindrone	Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.

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Inhibitors of CYP3A4 and CYP2D6
Clinical Impact:	The concomitant use of oxycodone hydrochloride tablets and CYP3A4 inhibitors can increase the plasma concentration of oxycodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of oxycodone hydrochloride tablets and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of oxycodone hydrochloride tablets is achieved [see Warnings and Precautions (5.4)]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the oxycodone plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to oxycodone.
Intervention:	If concomitant use is necessary, consider dosage reduction of oxycodone hydrochloride tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the oxycodone hydrochloride tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples:	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir).
CYP3A4 Inducers
Clinical Impact:	The concomitant use of oxycodone hydrochloride tablets and CYP3A4 inducers can decrease the plasma concentration of oxycodone [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to oxycodone [see Warnings and Precautions (5.12)]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the oxycodone plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention:	If concomitant use is necessary, consider increasing the oxycodone hydrochloride tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider oxycodone hydrochloride tablets dosage reduction and monitor for signs of respiratory depression.
Examples:	Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.5)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Adverse Reactions (6.2)].
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue oxycodone hydrochloride tablets if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
Intervention:	The use of oxycodone hydrochloride tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of oxycodone hydrochloride tablets and/or may precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use
Examples:	Butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Oxycodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of oxycodone hydrochloride tablets and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of dismissed diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant risk of anticholinergic drugs may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when oxycodone hydrochloride tablets are used concurrently with anticholinergic drugs.

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Table 3Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin	Monitor phenytoin level (7)
Methotrexate	Monitor for methotrexate toxicity (7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)

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Drugs That Interfere with Hemostasis
Clinical Impact:	• Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	• During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin dailyFor patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Interacting DrugInteracting Drug	InteractionInteraction
Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products.
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents	Carefully monitor blood glucose ( 5.11, 7.3)

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AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Table 2 Steady-State Plasma Concentrations of Felbatol When Coadministered With Other AEDs
*Not administered but an active metabolite of carbamazepine.
**No significant effect.
AED Coadministered	AED Concentration	Felbatol® Concentration
Phenytoin	↑	↓
Valproate	↑	↔**
Carbamazepine (CBZ) *CBZ epoxide	↓ ↑	↓
Phenobarbital	↑	↓

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Interacting Agent	Examples
Drugs whose efficacy is impaired by phenytoin
Azoles	Fluconazole, ketoconazole, itraconazole, posaconazole, voriconazole
Antineoplastic agents	Irinotecan, paclitaxel, teniposide
Delavirdine	Phenytoin can substantially reduce the concentrations of delavirdine. This can lead to loss of virologic response and possible resistance [see Contraindications (4)].
Neuromuscular blocking agents	Cisatracurium, pancuronium, rocuronium and vecuronium: resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents has occurred in patients chronically administered phenytoin. Whether or not phenytoin has the same effect on other non-depolarizing agents is unknown. Prevention or Management: Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher.
Warfarin	Increased and decreased PT/INR responses have been reported when phenytoin is co-administered with warfarin
Other	Corticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D
Drugs whose level is decreased by phenytoin
Antiepileptic drugs^a	Carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine
Antilipidemic agents	Atorvastatin, fluvastatin, simvastatin
Antiviral agents	Efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir Fosamprenavir: phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir.
Calcium channel blockers	Nifedipine, nimodipine, nisoldipine, verapamil
Other	Albendazole (decreases active metabolite), chlorpropamide, clozapine, cyclosporine, digoxin, folic acid, methadone, mexiletine, praziquantel, quetiapine

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Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Amiodarone, verapamil, diltiazem	Do not exceed 10 mg simvastatin daily
Amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (> 1 quart daily)

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Interacting Drug	Interaction
Valproic acid	Doripenem reduced the serum concentrations of valproic acid to below the therapeutic concentration range in healthy subjects (7.1)
Probenecid	Reduces renal clearance of doripenem, resulting in increased doripenem concentrations (7.2, 12.3)
Drugs metabolized by cytochrome P450 enzymes	Doripenem neither inhibits nor induces major cytochrome P450 enzymes (12.3)

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Table 4 Drugs Tested in In Vitro Binding or In Vivo Drug Interaction Testing or With Post-Marketing Reports
^a Should be administered at least 4 hours prior to WELCHOL
^b No significant alteration of warfarin drug levels with warfarin and WELCHOL coadministration in an in vivo study which did not evaluate warfarin pharmacodynamics (INR). [See Post-marketing Experience (6.2)]
^c Cyclosporine levels should be monitored and, based on theoretical grounds, cyclosporine should be administered at least 4 hours prior to WELCHOL.
Drugs with a known interaction with colesevelam	Cyclosporine^c, glyburide^a, levothyroxine^a, and oral contraceptives containing ethinyl estradiol and norethindrone^a
Drugs with postmarketing reports consistent with potential drug-drug interactions when coadministered with WELCHOL	phenytoin^a, warfarin^b
Drugs that do not interact with colesevelam based on in vitro or in vivo testing	cephalexin, ciprofloxacin, digoxin, warfarin^b fenofibrate, lovastatin, metformin, metoprolol, pioglitazone, quinidine, repaglinide, valproic acid, verapamil

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily*
Grapefruit juice	Avoid grapefruit juice

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
* Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol,	lomefloxacin
systemic and inhaled	mebendazole
amoxicillin	medroxyprogesterone
ampicillin,	methylprednisolone
with or without sulbactam	metronidazole
atenolol	metoprolol
azithromycin	nadolol
Caffeine,	nifedipine
dietary ingestion	nizatidine
cefactor	norfloxacin
co-trimoxazole	ofloxacin
(trimethoprim and	omeprazole
sulfamethoxazole)	prednisone, prednisolone
diltiazem	ranitidine
dirithromycin	rifabutin
enflurane	roxithromycin
famotidine	sorbitol
felodipine	(purgative doses do not
finasteride	inhibit theophylline
hydrocortisone	absorption)
isoflurane	sucralfate
isoniazid terbutaline,	systemic
isradipine	terfenadine
influenza vaccine	tetracycline
ketoconazole	tocainide

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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CYP2C19 or CYP3A4 Inducers
Clinical Impact:	Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention:	St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions (5.9)]. Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:	Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
Intervention:	Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
* For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily*
Grapefruit juice	Avoid grapefruit juice

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin	Monitor phenytoin level (7)
Methotrexate	Monitor for methotrexate toxicity (7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine (7)

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Table 7 Summary of AED Interactions with Oxcarbazepine Tablets, USP
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Tablets Dose (mg/day)	Influence of Oxcarbazepine Tablets on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400-2000	900	ncnc denotes a mean change of less than 10%	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100-150	600-1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250-500	600-1800 >1200-2400	nc ^, Pediatrics up to 40% increaseMean increase in adults at high oxcarbazepine tablets, USP doses [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400-2800	600-1800	nc	18% decrease [CI: 13% decrease, 40% decrease]

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 7.8, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 Inhibitors, (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with VYTORIN
Verapamil, diltiazem, dronedarone	Do not exceed 10/10 mg VYTORIN daily
Amiodarone, amlodipine, ranolazine	Do not exceed 10/20 mg VYTORIN daily
Lomitapide	For patients with HoFH, do not exceed 10/20 mg VYTORIN dailyFor patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 10/40 mg VYTORIN when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Table 18. Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9- Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Co-administered Drug	Dosing Schedule		Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference)		Risperidone Dose Recommendation
	Co-administered Drug	Risperidone	AUC	C_max
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Beta-Blockers
Clinical Impact:	The concomitant use of beta-blockers and Glucagon for Injection may increase the risk of a temporary increase in heart rate and blood pressure.
Intervention:	The increase in blood pressure and heart rate may require therapy in patients with coronary artery disease.
Insulin
Clinical Impact:	Insulin reacts antagonistically towards glucagon.
Intervention:	Monitor blood glucose when Glucagon for Injection is used as a diagnostic aid in diabetes patients.
Indomethacin
Clinical Impact:	The concomitant use of indomethacin and Glucagon for Injection may lead to hypoglycemia.
Intervention:	Monitor blood glucose levels during glucagon treatment of patients taking indomethacin.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs and Glucagon for Injection increase the risk of gastrointestinal adverse reactions due to additive effects on inhibition of gastrointestinal motility.
Intervention:	Concomitant use is not recommended.
Warfarin
Clinical Impact:	Glucagon may increase the anticoagulant effect of warfarin.
Intervention:	Monitor patients for unusual bruising or bleeding, as adjustments in warfarin dosage may be required.

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Drug	Description of Interaction
Tolbutamide; Sulfonylureas	Hypoglycemia potentiated
Methotrexate	Decreases tubular reabsorption; clinical toxicity from methotrexate can result
Oral Anticoagulant	Increased bleeding

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Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate[see Warnings and Precautions (5.6).]
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [see Adverse Reactions (6.1).]
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution 2-fold increase in exposure	Monitor for sildenafil toxicity (see Pharmacokinetics -(12.3)-].
Duloxetine	Avoid Use 5-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx^® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2)].	Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

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Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs that Interfere with Hemostasis
Clinical Impact :	Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention :	Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions ( 5 . 11)].
Aspirin
Clinical Impact :	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions ( 5 . 2)].
Intervention :	Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions ( 5 . 11)]. Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors , Angiotensin Receptor Blockers , or Beta - Blockers
Clinical Impact :	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention :	During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions ( 5 . 6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact :	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention :	During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions ( 5 . 6)].
Lithium
Clinical Impact :	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology ( 12 . 3)].
Intervention :	During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact :	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention :	During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact :	Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention :	During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact :	Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions ( 5 . 2)].
Intervention :	The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact :	Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention :	During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of this product. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.12, 7.3)

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidibetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Table 5. Clinically-Significant Drug Interactions with Sertraline Hydrochloride
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	The concomitant use of SSRIs including sertraline hydrochloride and MAOIs increases the risk of serotonin syndrome.
Intervention:	Sertraline hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [See Dosage and Administration (2.5), Contraindications (4), Warnings and Precautions (5.2)].
Examples:	selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
Pimozide
Clinical Impact:	Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QT prolongation and ventricular arrhythmias.
Intervention:	Concomitant use of pimozide and sertraline hydrochloride is contraindicated [See Contraindications (4)].
Other Serotonergic Drugs
Clinical Impact:	The concomitant use of serotonergic drugs with sertraline hydrochloride increases the risk of serotonin syndrome.
Intervention:	Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of sertraline hydrochloride and/or concomitant serotonergic drugs [See Warnings and Precautions (5.2)].
Examples:	other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort
Drugs that Interfere with Hemostasis (antiplatelet agents and anticoagulants)
Clinical Impact:	The concurrent use of an antiplatelet agent or anticoagulant with sertraline hydrochloride may potentiate the risk of bleeding.
Intervention:	Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [See Warnings and Precautions (5.3)].
Examples:	aspirin, clopidogrel, heparin, warfarin
Drugs Highly Bound to Plasma Protein
Clinical Impact:	Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of sertraline hydrochloride with another drug that is highly bound to plasma protein may increase free concentrations of sertraline hydrochloride or other tightly-bound drugs in plasma [See Clinical Pharmacology (12.3)] .
Intervention:	Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs as warranted.
Examples:	warfarin
Drugs Metabolized by CYP2D6
Clinical Impact:	Sertraline hydrochloride is a CYP2D6 inhibitor [See Clinical Pharmacology (12.3)] . The concomitant use of sertraline hydrochloride with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate.
Intervention:	Decrease the dosage of a CYP2D6 substrate if needed with concomitant sertraline hydrochloride use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride is discontinued.
Examples:	propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine
Phenytoin
Clinical Impact:	Phenytoin is a narrow therapeutic index drug. Sertraline hydrochloride may increase phenytoin concentrations.
Intervention:	Monitor phenytoin levels when initiating or titrating sertraline hydrochloride. Reduce phenytoin dosage if needed.
Examples:	phenytoin, fosphenytoin

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Table 4 Drugs Having Clinically Important Interactions with Amphetamines
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact	Concomitant use of MAOIs and CNS stimulants can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure.
Intervention	Do not administer dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate and amphetamine sulfate extended-release capsules concomitantly or within 14 days after discontinuing MAOI [see CONTRAINDICATIONS (4) and WARNINGS AND PRECAUTIONS (5.6)].
Examples	selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
Serotonergic Drugs
Clinical Impact	The concomitant use of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate and amphetamine sulfate extended-release capsules and serotonergic drugs increases the risk of serotonin syndrome.
Intervention	Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome, particularly during dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate and amphetamine sulfate extended-release capsules initiation or dosage increase. If serotonin syndrome occurs, discontinue dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate and amphetamine sulfate extended-release capsules and the concomitant serotonergic drug(s) [see WARNINGS AND PRECAUTIONS (5.6)].
Examples	selective serotonin reuptake inhibitors (SSRI), serotonin norepinephrine reuptake inhibitors (SNRI), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort
CYP2D6 Inhibitors
Clinical Impact	The concomitant use of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate and amphetamine sulfate extended-release capsules and CYP2D6 inhibitors may increase the exposure of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate and amphetamine sulfate extended-release capsules compared to the use of the drug alone and increase the risk of serotonin syndrome.
Intervention	Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome particularly during dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate and amphetamine sulfate extended-release capsules initiation and after a dosage increase. If serotonin syndrome occurs, discontinue dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate and amphetamine sulfate extended-release capsules and the CYP2D6 inhibitor [see WARNINGS AND PRECAUTIONS (5.6) and OVERDOSAGE (10)].
Examples	paroxetine and fluoxetine (also serotonergic drugs), quinidine, ritonavir
Alkalinizing Agents
Clinical Impact	Increase blood levels and potentiate the action of amphetamine.
Intervention	Co-administration of dextroamphetamine saccharate, amphetamine aspartate monohydrate, dextroamphetamine sulfate and amphetamine sulfate extended-release capsules and gastrointestinal or urinary alkalinizing agents should be avoided.
Examples	Gastrointestinal alkalinizing agents (e.g., sodium bicarbonate). Urinary alkalinizing agents (e.g. acetazolamide, some thiazides).
Acidifying Agents
Clinical Impact	Lower blood levels and efficacy of amphetamines.
Intervention	Increase dose based on clinical response.
Examples	Gastrointestinal acidifying agents (e.g., guanethidine, reserpine, glutamic acid HCl, ascorbic acid). Urinary acidifying agents (e.g., ammonium chloride, sodium acid phosphate, methenamine salts).
Tricyclic Antidepressants
Clinical Impact	May enhance the activity of tricyclic or sympathomimetic agents causing striking and sustained increases in the concentration of d-amphetamine in the brain; cardiovascular effects can be potentiated.
Intervention	Monitor frequently and adjust or use alternative therapy based on clinical response.
Examples	desipramine, protriptyline
Proton Pump Inhibitors
Clinical Impact	Time to maximum concentration (Tmax) of amphetamine is decreased compared to when administered alone.
Intervention	Monitor patients for changes in clinical effect and adjust therapy based on clinical response.
Examples	omeprazole

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of this product. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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AED Co-administered	AED Concentration	Topiramate Concentration
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
Phenytoin	NC or 25% increase = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide = Is not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Table 5 Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours in healthy adult subjects (n=24)
Concomitant Drug	C_maxSS (Peak plasma concentration)	AUCss_(0-12h) (Extent of systemic exposure)
Erythromycin (500 mg every 8 hrs)	+82%	+109%
Ketoconazole (400 mg once daily)	+135%	+164%

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Table II. Clinically significant drug interactions with theophylline.Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
Drug	Type of Interaction	EffectAverage effect on steady-state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine	Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.
Alcohol	A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours.	30% increase
Allopurinol	Decreases theophylline clearance at allopurinol doses ≥600 mg/day.	25% increase
Aminoglutethimide	Increases theophylline clearance by induction of microsomal enzyme activity.	25% decrease
Carbamazepine	Similar to aminoglutethimide.	30% decrease
Cimetidine	Decreases theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase
Ciprofloxacin	Similar to cimetidine.	40% increase
Clarithromycin	Similar to erythromycin.	25% increase
Diazepam	Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.	Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram	Decreases theophylline clearance by inhibiting hydroxylation and demethylation.	50% increase
Enoxacin	Similar to cimetidine.	300% increase
Ephedrine	Synergistic CNS effects	Increased frequency of nausea, nervousness, and insomnia.
Erythromycin	Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen	Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.	30% increase
Flurazepam	Similar to diazepam.	Similar to diazepam.
Fluvoxamine	Similar to cimetidine.	Similar to cimetidine.
Halothane	Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.	Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A	Decreases theophylline clearance.	100% increase
Isoproterenol (IV)	Increase theophylline clearance.	20% increase
Ketamine	Pharmacologic	May lower theophylline seizure threshold.
Lithium	Theophylline increases renal lithium clearance.	Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam	Similar to diazepam.	Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.	20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine	Similar to disulfiram.	80% increase
Midazolam	Similar to diazepam.	Similar to diazepam.
Moricizine	Increases theophylline clearance.	25% decrease
Pancuronium	Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.	Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline	Decreases theophylline clearance.	30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.	25% decrease after two weeks of concurrent PB.
Phenytoin	Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.	Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone	Decreases theophylline clearance and pharmacologic interaction.	40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and pharmacologic interaction.	100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin	Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.	20 to 40% decrease
Sulfinpyrazone	Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.	20% increase
Tacrine	Similar to cimetidine, also increases renal clearance of theophylline.	90% increase
Thiabendazole	Decreases theophylline clearance.	190% increase
Ticlopidine	Decreases theophylline clearance.	60% increase
Troleandomycin	Similar to erythromycin.	33 to 100% increase depending on troleandomycin dose.
Verapamil	Similar to disulfiram.	20% increase

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. ₄ ₃
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT , is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. ₄ ₄ ₄ ₄ ₃ ₄ ₄ ₄
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. ₄
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T to T , leading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T and T levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). ₄ ₃ ₃ ₄ ₃ ₄ ₃ ₄ ₃ ₄
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of I, I, and Tc. ¹²³ ¹³¹ ^99m
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 2: Drug Interactions: Pharmacokinetic Parameters for Indinavir in the Presence of the Coadministered Drug (See PRECAUTIONS, Table 9 for Recommended Alterations in Dose or Regimen)
Coadministered drug	Dose of Coadministered drug (mg)	Dose of CRIXIVAN (mg)	n	Ratio (with/without coadministered drug) of Indinavir Pharmacokinetic Parameters (90% CI); No Effect = 1.00
				C_max	AUC	C_min
All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
Cimetidine	600 twice daily, 6 days	400 single dose	12	1.07 (0.77, 1.49)	0.98 (0.81, 1.19)	0.82 (0.69, 0.99)
Clarithromycin	500 q12h, 7 days	800 three times daily, 7 days	10	1.08 (0.85, 1.38)	1.19 (1.00, 1.42)	1.57 (1.16, 2.12)
Delavirdine	400 three times daily	400 three times daily, 7 days	28	0.64Relative to indinavir 800 mg three times daily alone. (0.48, 0.86)	No significant change	2.18 (1.16, 4.12)
Delavirdine	400 three times daily	600 three times daily, 7 days	28	No significant change	1.53 (1.07, 2.20)	3.98 (2.04, 7.78)
EfavirenzStudy conducted in HIV-positive subjects.	600 once daily, 10 days	1000 three times daily, 10 days	20
		After morning dose		No significant change	0.67 (0.61, 0.74)	0.61 (0.49, 0.76)
		After afternoon dose		No significant change	0.63 (0.54, 0.74)	0.48 (0.43, 0.53)
		After evening dose		0.71 (0.57, 0.89)	0.54 (0.46, 0.63)	0.43 (0.37, 0.50)
Fluconazole	400 once daily, 8 days	1000 three times daily, 7 days	11	0.87 (0.72, 1.05)	0.76 (0.59, 0.98)	0.90 (0.72, 1.12)
Grapefruit Juice	8 oz.	400 single dose	10	0.65 (0.53, 0.79)	0.73 (0.60, 0.87)	0.90 (0.71, 1.15)
Isoniazid	300 once daily in the morning, 8 days	800 three times daily, 7 days	11	0.95 (0.88, 1.03)	0.99 (0.87, 1.13)	0.89 (0.75, 1.06)
Itraconazole	200 twice daily, 7 days	600 three times daily, 7 days	12	0.78 (0.69, 0.88)	0.99 (0.91, 1.06)	1.49 (1.28, 1.74)
Ketoconazole	400 once daily, 7 days	600 three times daily, 7 days	12	0.69 (0.61, 0.78)	0.80 (0.74, 0.87)	1.29 (1.11, 1.51)
	400 once daily, 7 days	400 three times daily, 7 days	12	0.42 (0.37, 0.47)	0.44 (0.41, 0.48)	0.73 (0.62, 0.85)
Methadone	20-60 once daily in the morning, 8 days	800 three times daily, 8 days	10	See text below for discussion of interaction.
Quinidine	200 single dose	400 single dose	10	0.96 (0.79, 1.18)	1.07 (0.89, 1.28)	0.93 (0.73, 1.19)
Rifabutin	150 once daily in the morning, 10 days	800 three times daily, 10 days	14	0.80 (0.72, 0.89)	0.68 (0.60, 0.76)	0.60 (0.51, 0.72)
Rifabutin	300 once daily in the morning, 10 days	800 three times daily, 10 days	10	0.75 (0.61, 0.91)	0.66 (0.56, 0.77)	0.61 (0.50, 0.75)
Rifampin	600 once daily in the morning, 8 days	800 three times daily, 7 days	12	0.13 (0.08, 0.22)	0.08 (0.06, 0.11)	Not Done
Ritonavir	100 twice daily, 14 days	800 twice daily, 14 days	10, 16Comparison to historical data on 16 subjects receiving indinavir alone.	See text below for discussion of interaction.
Ritonavir	200 twice daily, 14 days	800 twice daily,14 days	9, 16	See text below for discussion of interaction.
Sildenafil	25 single dose	800 three times daily	6	See text below for discussion of interaction.
St. John's wort (Hypericum perforatum, standardized to 0.3 % hypericin)	300 three times daily with meals, 14 days	800 three times daily	8	Not Available	0.46 (0.34, 0.58)95% CI.	0.19 (0.06, 0.33)
Stavudine (d4T)	40 twice daily, 7 days	800 three times daily, 7 days	11	0.95 (0.80, 1.11)	0.95 (0.80, 1.12)	1.13 (0.83, 1.53)
Trimethoprim/ Sulfamethoxazole	800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days	400 four times daily, 7 days	12	1.12 (0.87, 1.46)	0.98 (0.81, 1.18)	0.83 (0.72, 0.95)
Zidovudine	200 three times daily, 7 days	1000 three times daily, 7 days	12	1.06 (0.91, 1.25)	1.05 (0.86, 1.28)	1.02 (0.77, 1.35)
Zidovudine/ Lamivudine (3TC)	200/150 three times daily, 7 days	800 three times daily, 7 days	6, 9Parallel group design; n for indinavir + coadministered drug, n for indinavir alone.	1.05 (0.83, 1.33)	1.04 (0.67, 1.61)	0.98 (0.56, 1.73)

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine, danazol	Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem	Do not exceed 40 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
* The interaction between immediate-release nevirapine and the drug was evaluated in a clinical study. The results of drug interaction studies with immediate-release nevirapine are expected to also apply to nevirapine extended-release tablets.
Drug Name	Effect on Concentration of Nevirapine or Concomitant Drug	Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir*	↓ Atazanavir ↑ Nevirapine	Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir* Fosamprenavir/Ritonavir*	↓ Amprenavir ↑ Nevirapine ↓ Amprenavir ↑ Nevirapine	Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir*	↓ Indinavir	The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir*	↓Lopinavir	Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra^® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir*	↓ Nelfinavir M8 Metabolite ↓ Nelfinavir C_min	The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/ritonavir	The interaction between nevirapine and saquinavir/ritonavir has not been evaluated	The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz*	↓ Efavirenz	The appropriate doses of these combinations with respect to safety and efficacy have not been established.
Delavirdine Etravirine Rilpivirine		Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.
Hepatitis C Antiviral Agents
Boceprevir	Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine.	Nevirapine and boceprevir should not be coadministered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy.
Telaprevir	Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir.	Nevirapine and telaprevir should not be coadministered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events.
Other Agents
Analgesics: Methadone*	↓ Methadone	Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics: Amiodarone, disopyramide, lidocaine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Antibiotics: Clarithromycin*	↓ Clarithromycin ↑ 14-OH clarithromycin	Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Rifabutin*	↑ Rifabutin	Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin*	↓ Nevirapine	Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants: Carbamazepine, clonazepam, ethosuximide	Plasma concentrations of nevirapine and the anticonvulsant may be decreased.	Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals: Fluconazole*	↑ Nevirapine	Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Ketoconazole*	↓ Ketoconazole	Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Itraconazole	↓ Itraconazole	Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics: Warfarin	Plasma concentrations may be increased.	Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers: Diltiazem, nifedipine, verapamil	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Cancer chemotherapy: Cyclophosphamide	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Ergot alkaloids: Ergotamine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Motility agents: Cisapride	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Opiate agonists: Fentanyl	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Oral contraceptives: Ethinyl estradiol and Norethindrone*	↓ Ethinyl estradiol ↓ Norethindrone	Despite lower ethinyl estradiol and norethindrone exposures when coadministered with nevirapine, literature reports suggest that nevirapine has no effect on pregnancy rates among HIV-infected women on combined oral contraceptives. When coadministered with nevirapine extended-release tablets, no dose adjustment of ethinyl estradiol or norethindrone is needed when used in combination for contraception. When oral contraceptives are used for hormonal regulation during nevirapine extended-release tablets therapy, the therapeutic effect of the hormonal therapy should be monitored.

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Table 3: Clinically Relevant Interactions Affecting Drugs Co-Administered with Omeprazole and Interaction with Diagnostics
Antiretrovirals
Clinical Impact:	The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology ( 12.3)]. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)]. There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
Intervention:	Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications ( 4)] . Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:	Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention:	Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact:	Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions ( 5.11)].
Intervention:	A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact:	Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology ( 12.3)]. There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel .
Intervention:	Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions ( 5.6)].
Citalopram
Clinical Impact:	Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology ( 12.3)] .
Intervention:	Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:	Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology ( 12.3)].
Intervention:	Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:	Potential for increased exposure of phenytoin.
Intervention:	Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:	Increased exposure of diazepam [see Clinical Pharmacology ( 12.3)] .
Intervention:	Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:	Potential for increased exposure of digoxin [see Clinical Pharmacology ( 12.3)].
Intervention:	Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:	Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:	Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology ( 12.3)] . See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:	Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:	See Contraindications, Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact:	Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19 .
Intervention:	Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:	Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions ( 5.10), Clinical Pharmacology ( 12.2)] .
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:	Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology ( 12.2)] .
False Positive Urine Tests for THC
Clinical Impact:	There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:	An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:	There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:	Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.

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* For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily*
Grapefruit juice	Avoid grapefruit juice

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Interacting DrugInteracting Drug	InteractionInteraction
Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.12, 7.3)

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CYP2C19 or CYP3A4 Inducers
Clinical Impact:	Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology ( 12.3)] .
Intervention:	St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions ( 5.9)] . Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:	Increased exposure of omeprazole [see Clinical Pharmacology ( 12.3)] .
Intervention:	Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole.

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Table 14: Clinically Important Drug Interactions: Effect of other Drugs on Guanfacine Extended-Release Tablets
Concomitant Drug Name or Drug Class	Clinical Rationale and Magnitude of Drug Interaction	Clinical Recommendation
CYP3A4 inhibitors, e.g.,ketoconazole	Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in a 200% increase in exposure	Consider dose reduction [see Dosage and Administration (2.7)]
CYP3A4 inducers, e.g., rifampin	Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in a 60% decrease in exposure	Consider dose increase [see Dosage and Administration (2.7)]

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Table 3 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 4 for Magnitude of Interaction.
Drug Name	Effect on Concentration of Nevirapine or Concomitant Drug	Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir*	↓ Atazanavir ↑ Nevirapine	Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir* Fosamprenavir/Ritonavir*	↓ Amprenavir ↑ Nevirapine ↓ Amprenavir ↑ Nevirapine	Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir*	↓ Indinavir	The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir*	↓Lopinavir	Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir*	↓Nelfinavir M8 Metabolite ↓Nelfinavir C_min	The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/ritonavir	The interaction between Nevirapine and saquinavir/ritonavir has not been evaluated	The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz* Delavirdine Etravirine Rilpivirine	↓ Efavirenz	The appropriate doses of these combinations with respect to safety and efficacy have not been established. Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.
Other Agents
Analgesics: Methadone*	↓ Methadone	Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics: Amiodarone, disopyramide, lidocaine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Antibiotics: Clarithromycin* Rifabutin* Rifampin*	↓ Clarithromycin ↑ 14-OH clarithromycin ↑ Rifabutin ↓ Nevirapine	Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered. Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants: Carbamazepine, clonazepam, ethosuximide	Plasma concentrations of nevirapine and the anticonvulsant may be decreased.	Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals: Fluconazole* Ketoconazole* Itraconazole	↑Nevirapine ↓ Ketoconazole ↓ Itraconazole	Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events. Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics: Warfarin	Plasma concentrations may be increased.	Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers: Diltiazem, nifedipine, verapamil	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Cancer chemotherapy: Cyclophosphamide	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Ergot alkaloids: Ergotamine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Motility agents: Cisapride	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Opiate agonists: Fentanyl	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Oral contraceptives: Ethinyl estradiol and Norethindrone*	↓ Ethinyl estradiol ↓ Norethindrone	Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.
* The interaction between Nevirapine and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.

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Table II. Clinically significant drug interactions with theophylline*.
* Refer to PRECAUTIONS , Drug Interactions for further information regarding table. ** Average effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Drug	Type of Interaction	Effect**
Adenosine	Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.
Alcohol	A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours.	30% increase
Allopurinol	Decreases theophylline clearance at allopurinol doses ≥ 600 mg/day.	25% increase
Aminoglutethimide	Increases theophylline clearance by induction of microsomal enzyme activity.	25% decrease
Carbamazepine	Similar to aminoglutethimide.	30% decrease
Cimetidine	Decreases theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase
Ciprofloxacin	Similar to cimetidine.	40% increase
Clarithromycin	Similar to erythromycin.	25% increase
Diazepam	Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.	Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram	Decreases theophylline clearance by inhibiting hydroxylation and demethylation.	50% increase
Enoxacin	Similar to cimetidine.	300% increase
Ephedrine	Synergistic CNS effects.	Increased frequency of nausea, nervousness, and insomnia.
Erythromycin	Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen	Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.	30% increase
Flurazepam	Similar to diazepam.	Similar to diazepam.
Fluvoxamine	Similar to cimetidine.	Similar to cimetidine.
Halothane	Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.	Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A	Decreases theophylline clearance.	100% increase
Isoproterenol (IV)	Increases theophylline clearance.	20% decrease
Ketamine	Pharmacologic	May lower theophylline seizure threshold.
Lithium	Theophylline increases renal lithium clearance.	Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam	Similar to diazepam.	Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.	20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine	Similar to disulfiram.	80% increase
Midazolam	Similar to diazepam.	Similar to diazepam.
Moricizine	Increases theophylline clearance.	25% decrease
Pancuronium	Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.	Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline	Decreases theophylline clearance.	30% increase
Phenobarbital	Similar to aminoglutethimide.	25% decrease after two weeks of concurrent Phenobarbital.
Phenytoin	Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.	Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone	Decreases theophylline clearance and pharmacologic interaction.	40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and pharmacologic interaction.	100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin	Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.	20-40% decrease
Sulfinpyrazone	Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.	20% decrease
Tacrine	Similar to cimetidine, also increases renal clearance of theophylline.	90% increase
Thiabendazole	Decreases theophylline clearance.	190% increase
Ticlopidine	Decreases theophylline clearance.	60% increase
Troleandomycin	Similar to erythromycin.	33-100% increase depending on troleandomycin dose.
Verapamil	Similar to disulfiram.	20% increase

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin	Monitor phenytoin level (7)
Methotrexate	Monitor for methotrexate toxicity (7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation- containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
*Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	C _m _a _x
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing.
	20 mg/day	4 mg/day	1.6	-	Do not exceed 8 mg/day
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers)
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Factors	Dosage Adjustments for Aripiprazole Tablets
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors	Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double usual dose over 1 to 2 weeks

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Figure 1: Effect of interacting drugs on the pharmacokinetics of venlafaxine and active metabolite O-desmethylvenlafaxine (ODV).

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Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs that Interfere with Hemostasis
Clinical Impact :	Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention :	Monitor patients with concomitant use of Meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact :	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention :	Concomitant use of Meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors , Angiotensin Receptor Blockers , or Beta - Blockers
Clinical Impact :	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention :	During concomitant use of Meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of Meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact :	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention :	During concomitant use of Meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Lithium
Clinical Impact :	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology (12.3)].
Intervention :	During concomitant use of Meloxicam and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact :	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention :	During concomitant use of Meloxicam and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact :	Concomitant use of Meloxicam and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention :	During concomitant use of Meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact :	Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention :	The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact :	Concomitant use of Meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention :	During concomitant use of Meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.

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NA – Not available/reported
Digoxin concentrations increased greater than 50%
	Digoxin Serum Concentration Increase	Digoxin AUC Increase	Recommendations
Amiodarone	70%	NA	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
Captopril	58%	39%
Clarithromycin	NA	70%
Dronedarone	NA	150%
Gentamicin	129-212%	NA
Erythromycin	100%	NA
Itraconazole	80%	NA
Lapatinib	NA	180%
Propafenone	NA	60-270%
Quinidine	100%	NA
Ranolazine	50%	NA
Ritonavir	NA	86%
Telaprevir	50%	85%
Tetracycline	100%	NA
Verapamil	50-75%	NA
Digoxin concentrations increased less than 50%
Atorvastatin	22%	15%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
Carvedilol	16%	14%
Conivaptan	33%	43%
Diltiazem	20%	NA
Indomethacin	40%	NA
Nefazodone	27%	15%
Nifedipine	45%	NA
Propantheline	24%	24%
Quinine	NA	33%
Rabeprazole	29%	19%
Saquinavir	27%	49%
Spironolactone	25%	NA
Telmisartan	20-49%	NA
Ticagrelor	31%	28%
Tolvaptan	30%	20%
Trimethoprim	22-28%	NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate, sulfasalazine			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20-40% as necessary.

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Bleeding times
Clinical Impact:	Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention:	This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact:	The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention:	Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact:	Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention:	This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.

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AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide Is not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T ₄ and T ₃levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT ₄ . Continued administration results in a decrease in serum T ₄ and normal FT ₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T ₄ and T ₃ to TBG and transthyretin. An initial increase in serum FT ₄ is followed by return of FT ₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T ₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T ₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T ₄ to T ₃, leading to decreased T ₃ levels. However, serum T ₄levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T ₃ and T ₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T ₃concentrations by 30% with minimal change in serum T ₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T ₃ and T ₄levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³ I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 2. Drugs That May Decrease T4 Absorption (Hypothyroidism)
Potential impact: Concurrent use may reduce the efficacy of SYNTHROID by binding and delaying or preventing absorption, potentially resulting in hypothyroidism.
Drug or Drug Class	Effect
Calcium Carbonate Ferrous Sulfate	Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer SYNTHROID at least 4 hours apart from these agents.
Orlistat	Monitor patients treated concomitantly with orlistat and SYNTHROID for changes in thyroid function.
Bile Acid Sequestrants - Colesevelam - Cholestyramine - Colestipol Ion Exchange Resins - Kayexalate - Sevelamer	Bile acid sequestrants and ion exchange resins are known to decrease levothyroxine absorption. Administer SYNTHROID at least 4 hours prior to these drugs or monitor TSH levels.
Other drugs: Proton Pump Inhibitors Sucralfate Antacids - Aluminum & Magnesium Hydroxides - Simethicone	Gastric acidity is an essential requirement for adequate absorption of levothyroxine. Sucralfate, antacids and proton pump inhibitors may cause hypochlorhydria, affect intragastric pH, and reduce levothyroxine absorption. Monitor patients appropriately.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Drug	Description
Corticosteroids	Decreases plasma salicylate level; tapering doses of steroids may promote salicylism
Ammonium Sulfate	Increases plasma salicylate level

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol,	famotidine	nizatidine
systemic and inhaled	felodipine	norfloxacin
amoxicillin	finasteride	ofloxacin
ampicillin,	hydrocortisone	omeprazole
with or without	isoflurane	prednisone, prednisolone
sulbactam	isoniazid	ranitidine
atenolol	isradipine	rifabutin
azithromycin	influenza vaccine	roxithromycin
caffeine,	ketoconazole	sorbitol
dietary digestion	lomefloxacin	(purgative doses do not
cefaclor	mebendazole	inhibit theophylline
co-trimoxazole	medroxyprogesterone	absorption)
(trimethoprim and	methylprednisolone	sucralfate
sulfamethoxazole)	metronidazole	terbutaline, systemic
diltiazem	metoprolol	terfenadine
dirithromycin	nadolol	tetracycline
enflurane	nifedipine	tocainide

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Factors	Dosage Adjustment of ABILIFY
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors	Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double usual dose over 1 to 2 weeks

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Table 6. Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology ( 12.3)]
Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (C _max and AUC _τ after 200 mg q12h)	Recommendations for Voriconazole Dosage Adjustment/Comments
Rifampin Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects and Rifabutin (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (400 mg q 24h) Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects (CYP450 Induction) Efavirenz (300 mg q 24h) (CYP450 Induction)	Significantly Reduced Slight decrease in AUC _t	Contraindicated When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h) (CYP450 Induction)	Significantly Reduced	Contraindicated
Low-dose Ritonavir (100 mg q12h) (CYP450 Induction)	Reduced	Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Phenytoin (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John’s Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIs Non-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to voriconazole
	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Careful assessment of voriconazole effectiveness

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Table 2: Drug-Thyroidal Axis Interactions
	Drug or Drug Class		Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
		Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
		Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
		Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
		Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
		Amiodarone Iodide (including iodine- containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
	Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
	Drugs that may increase		Drugs that may decrease
	serum TBG concentration		serum TBG concentration
	Clofibrate		Androgens / Anabolic Steroids
	Estrogen-containing oral		Asparaginase
	contraceptives		Glucocorticoids
	Estrogens (oral)		Slow-Release Nicotinic Acid
	Heroin / Methadone
	5-Fluorouracil
	Mitotane
	Tamoxifen
	Drugs that may cause protein-binding site displacement
	Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)		Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
	Carbamazepine Hydantoins Phenobarbital Rifampin		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
	Drugs that may decrease T ₄ 5' - deiodinase activity
	Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)		Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, Ieading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
	Miscellaneous
	Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives		Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
	Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
	Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin		Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
	Cardiac Glycosides		Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
	Cytokines - Interferon-α - Interleukin-2		Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
	Growth Hormones - Somatrem - Somatropin		Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
	Ketamine		Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
	Methylxanthine Bronchodilators - (e.g., Theophylline)		Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
	Radiographic Agents		Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
	Sympathomimetics		Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
	Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics		These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 2 Rifabutin Interaction Studies
Coadministered drug	Dosing regimen of coadministered drug	Dosing regimen of rifabutin	Study population (n)	Effect on rifabutin	Effect on coadministered drug	Recommendation
↑ indicates increase; ↓ indicates decrease; ↔ indicates no significant change QD- once daily; BID- twice daily; TID – thrice daily ND - No Data AUC - Area under the Concentration vs. Time Curve; C_max - Maximum serum concentration
ANTIVIRALS
Amprenavir	1200 mg BID × 10 days	300 mg QD × 10 days	Healthy male subjects (6)	↑ AUC by 193%, ↑ Cmax by 119%	↔	Reduce rifabutin dose by at least 50%. Monitor closely for adverse reactions.
Delavirdine	400 mg TID	300 mg QD	HIV-infected patients (7)	↑ AUC by 230%, ↑ Cmax by 128%	↓ AUC by 80%, ↓ Cmax by 75%, ↓ Cmin by 17%	CONTRAINDICATED
Didanosine	167 or 250 mg BID × 12 days	300 or 600 mg QD × 1	HIV-infected patients (11)	↔	↔
Fosamprenavir/ ritonavir	700 mg BID plus ritonavir 100 mg BID × 2 weeks	150 mg every other day × 2 weeks	Healthy subjects (15)	↔ AUCcompared to rifabutin 300 mg QD alone ↓ Cmax by 15%	↑ AUC by 35%compared to historical control (fosamprenavir/ritonavir 700/100 mg BID), ↑ Cmax by 36%, ↑ Cmin by 36%,	Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with fosamprenavir/ritonavir combination.
Indinavir	800 mg TID × 10 days	300 mg QD × 10 days	Healthy subjects (10)	↑ AUC by 173%, ↑ Cmax by 134%	↓ AUC by 34%, ↓ Cmax by 25%, ↓ Cmin by 39%	Reduce rifabutin dose by 50%, and increase indinavir dose from 800 mg to 1000 mg TID.
Lopinavir/ ritonavir	400/100 mg BID × 20 days	150 mg QD × 10 days	Healthy subjects (14)	↑ AUC by 203% also taking zidovudine 500 mg QD ↓ Cmax by 112%	↔	Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed.
Saquinavir/ ritonavir	1000/100 mg BID × 14 or 22 days	150 mg every 3 days × 21–22 days	Healthy subjects	↑ AUC by 53% compared to rifabutin 150 mg QD alone ↑ Cmax by 88% (n=11)	↓ AUC by 13%, ↓ Cmax by 15%, (n=19)	Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with saquinavir/ritonavir combination. Monitor closely for adverse reactions.
Ritonavir	500 mg BID × 10 days	150 mg QD × 16 days	Healthy subjects (5)	↑ AUC by 300%, ↑ Cmax by 150%	ND	Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed.
Tipranavir/ ritonavir	500/200 BID × 15 doses	150 mg single dose	Healthy subjects (20)	↑ AUC by 190%, ↑ Cmax by 70%	↔	Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with tipranavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed.
Nelfinavir	1250 mg BID × 7–8 days	150 mg QD × 8 days	HIV-infected patients (11)	↑ AUC by 83%, compared to rifabutin 300 mg QD alone ↑ Cmax by 19%	↔	Reduce rifabutin dose by 50% (to 150 mg QD) and increase the nelfinavir dose to 1250 mg BID
Zidovudine	100 or 200 mg q4h	300 or 450 mg QD	HIV-infected patients (16)	↔	↓ AUC by 32%, ↓ Cmax by 48%,	Because zidovudine levels remained within the therapeutic range during coadministration of rifabutin, dosage adjustments are not necessary.
ANTIFUNGALS
Fluconazole	200 mg QD × 2 weeks	300 mg QD × 2 weeks	HIV-infected patients (12)	↑ AUC by 82%, ↑ Cmax by 88%	↔	Monitor for rifabutin associated adverse events. Reduce rifabutin dose or suspend MYCOBUTIN use if toxicity is suspected.
Posaconazole	200 mg QD × 10 days	300 mg QD × 17 days	Healthy subjects (8)	↑ AUC by 72%, ↑ Cmax by 31%	↓ AUC by 49%, ↓ Cmax by 43%	If co-administration of these two drugs cannot be avoided, patients should be monitored for adverse events associated with rifabutin administration, and lack of posaconazole efficacy.
Itraconazole	200 mg QD	300 mg QD	HIV-Infected patients (6)	↑data from a case report	↓ AUC by 70%, ↓ Cmax by 75%,	If co-administration of these two drugs cannot be avoided, patients should be monitored for adverse events associated with rifabutin administration, and lack of itraconazole efficacy. In a separate study, one case of uveitis was associated with increased serum rifabutin levels following co-administration of rifabutin (300 mg QD) with itraconazole (600–900 mg QD).
Voriconazole	400 mg BID × 7 days (maintenance dose)	300 mg QD × 7 days	Healthy male subjects (12)	↑ AUC by 331%, ↑ Cmax by 195%	↑ AUC by ~100%, ↑ Cmax by ~100%compared to voriconazole 200 mg BID alone	CONTRAINDICATED
ANTI-PCP (Pneumocystis carinii pneumonia)
Dapsone	50 mg QD	300 mg QD	HIV-infected patients (16)	ND	↓ AUC by 27 –40%
Sulfamethoxazole- Trimethoprim	800/160 mg	300 mg QD	HIV-infected patients (12)	↔	↓ AUC by 15–20%
ANTI-MAC (Mycobacterium avium intracellulare complex)
Azithromycin	500 mg QD × 1 day, then 250 mg QD × 9 days	300 mg QD	Healthy subjects (6)	↔	↔
Clarithromycin	500 mg BID	300 mg QD	HIV-infected patients (12)	↑ AUC by 75%	↓ AUC by 50%	Monitor for rifabutin associated adverse events. Reduce dose or suspend use of MYCOBUTIN if toxicity is suspected. Alternative treatment for clarithromycin should be considered when treating patients receiving rifabutin
ANTI-TB (Tuberculosis)
Ethambutol	1200 mg	300 mg QD × 7 days	Healthy subjects (10)	ND	↔
Isoniazid	300 mg	300 mg QD × 7 days	Healthy subjects (6)	ND	↔
OTHER
Methadone	20 – 100 mg QD	300 mg QD × 13 days	HIV-infected patients (24)	ND	↔
Ethinylestradiol (EE)/Norethindrone (NE)	35 mg EE / 1 mg NE × 21 days	300 mg QD × 10 days	Healthy female subjects (22)	ND	EE: ↓ AUC by 35%, ↓ C_max by 20% NE: ↓ AUC by 46%	Patients should be advised to use additional or alternative methods of contraception.
Theophylline	5 mg/kg	300 mg × 14 days	Healthy subjects (11)	ND	↔

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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NA = Not available/reported
Digoxin concentrations increased greater than 50%
	Digoxin Serum Concentration Increase	Digoxin AUC Increase	Recommendations
Amiodarone	70%	NA	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
Captopril	58%	39%
Clarithromycin	NA	70%
Dronedarone	NA	150%
Gentamicin	129-212%	NA
Erythromycin	100%	NA
Itraconazole	80%	NA
Lapatinib	NA	180%
Nitrendipine	57%	15%
Propafenone	NA	60-270%
Quinidine	100%	NA
Ranolazine	50%	NA
Ritonavir	NA	86%
Telaprevir	50%	85%
Tetracycline	100%	NA
Verapamil	50-75%	NA
Digoxin concentrations increased less than 50%
Atorvastatin	22%	15%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
Carvedilol	16%	14%
Conivaptan	33%	43%
Diltiazem	20%	NA
Indomethacin	40%	NA
Nefazodone	27%	15%
Nifedipine	45%	NA
Propantheline	24%	24%
Quinine	NA	33%
Rabeprazole	29%	19%
Saquinavir	27%	49%
Spironolactone	25%	NA
Telmisartan	20-49%	NA
Ticagrelor	31%	28%
Tolvaptan	30%	20%
Trimethoprim	22-28%	NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate and sulfasalazine			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20-40% as necessary.

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DRUG	DESCRIPTION OF INTERACTION
Corticosteroids	Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents	Increases plasma salicylate level.
Alkalizing Agents	Decreased plasma salicylate levels.

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Table 3. Drugs That May Alter T4 and Triiodothyronine (T3) Serum Transport Without Affecting Free Thyroxine (FT4) Concentration (Euthyroidism)
Drug or Drug Class	Effect
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	These drugs may increase serum thyroxine-binding globulin (TBG) concentration.
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid	These drugs may decrease serum TBG concentration.
Potential impact (below): Administration of these agents with SYNTHROID results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations.
Salicylates (> 2 g/day)	Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total T4 levels may decrease by as much as 30%.
Other drugs: Carbamazepine Furosemide (> 80 mg IV) Heparin Hydantoins Non-Steroidal Anti-inflammatory Drugs - Fenamates	These drugs may cause protein-binding site displacement. Furosemide has been shown to inhibit the protein binding of T4 to TBG and albumin, causing an increase free T4 fraction in serum. Furosemide competes for T4-binding sites on TBG, prealbumin, and albumin, so that a single high dose can acutely lower the total T4 level. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total and free T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. Closely monitor thyroid hormone parameters.

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Table 3Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Table 7: Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]
^* Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects ^ Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects ^* Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30-100 mg q24h) ^** Non-Steroidal Anti-Inflammatory Drug ^*** Non-Nucleoside Reverse Transcriptase Inhibitors
Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C_max and AUC_τ)	Recommendations for Drug Dosage Adjustment/Comments
Sirolimus* (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin* (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (400 mg q24h) (CYP3A4 Inhibition) Efavirenz (300 mg q24h) (CYP3A4 Inhibition)	Significantly Increased Slight Increase inAUC_τ	Contraindicated When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h) (CYP3A4 Inhibition) Low-dose Ritonavir (100 mg q12h)	No Significant Effect of Voriconazole on Ritonavir C_max or AUC_τ Slight Decrease in Ritonavir C_max and AUC_τ	Contraindicated because of significant reduction of voriconazole C_max and AUC_τ Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole C_max and AUC_τ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated
Cyclosporine* (CYP3A4 Inhibition)	AUC_τ Significantly Increased; No Significant Effect on C_max	When initiating therapy with voriconazole tablets in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole tablets are discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
Methadone*** (CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazoletablets. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7)]
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole tablet. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see Drug Interactions (7)].
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazoletablets. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7)].
NSAIDs**** including ibuprofen and diclofenac (CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [see Drug Interactions (7)].
Tacrolimus* (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with voriconazole tablets in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazoletablets are discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin* (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)**	Increased	Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin* (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole* (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with voriconazoletablets in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects on Indinavir Exposure In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	No dosage adjustment for indinavir when coadministered with voriconazole tablets Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIs***** (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.
Everolimus (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Concomitant administration of voriconazole and everolimus is not recommended.

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CYP2C19 or CYP3A4 Inducers
Clinical Impact:	Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention:	St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions (5.9)]. Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:	Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
Intervention:	Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole.

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Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.9)].
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.11) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs [see Adverse Reactions (6.1)].
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions (5.16)].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution Two-fold increase in exposure	Monitor for sildenafil toxicity [see Clinical Pharmacology (12.3)].
Duloxetine	Avoid Use Five-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx^®(didanosine) chewable/ buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2.4)].	Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

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Antibiotics	Antineo-plastic	Antifungals	Anti-inflammatory Drugs	Gastro-intestinal Agents	Immuno-suppres- sives	Other Drugs
ciprofloxacin gentamicin tobramycin trimethoprim with sulfamethoxazole vancomycin	melphalan	amphotericin B ketoconazole	azapropazon colchicine diclofenac naproxen sulindac	cimetidine ranitidine	tacrolimus	fibric acid derivatives (e.g., bezafibrate, fenofibrate) methotrexate

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Name of the Concomitant Drug	Change in the Concentration of Ganciclovir or Concomitant Drug	Clinical Comment
Zidovudine	↓ Ganciclovir ↑ Zidovudine	Zidovudine and valganciclovir each have the potential to cause neutropenia and anemia
Probenecid	↑ Ganciclovir	Patients taking probenecid and valganciclovir should be monitored for evidence of ganciclovir toxicity
Mycophenolate Mofetil (MMF)	↔ Ganciclovir (in patients with normal renal function) ↔ MMF (in patients with normal renal function)	Patients with renal impairment should be monitored carefully as levels of MMF metabolites and ganciclovir may increase
Didanosine	↓ Ganciclovir ↑ Didanosine	Patients should be closely monitored for didanosine toxicity

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. ₄ ₃
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT , is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. ₄ ₄ ₄ ₄ ₃ ₄ ₄ ₄
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. ₄
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T to T , leading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T and T levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). ₄ ₃ ₃ ₄ ₃ ₄ ₃ ₄ ₃ ₄
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of I, I, and Tc. ¹²³ ¹³¹ ^99m
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

Table name:

Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)	Do not exceed 40 mg atorvastatin daily

Table name:

Name of the Concomitant Drug	Change in the Concentration of Ganciclovir or Concomitant Drug	Clinical Comment
Zidovudine	↓ Ganciclovir ↑ Zidovudine	Zidovudine and valganciclovir each have the potential to cause neutropenia and anemia
Probenecid	↑ Ganciclovir	Patients taking probenecid and valganciclovir should be monitored for evidence of ganciclovir toxicity
Mycophenolate Mofetil (MMF)	↔ Ganciclovir (in patients with normal renal function) ↔ MMF (in patients with normal renal function)	Patients with renal impairment should be monitored carefully as levels of MMF metabolites and ganciclovir may increase
Didanosine	↓ Ganciclovir ↑ Didanosine	Patients should be closely monitored for didanosine toxicity

Table name:

Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ Lamotrigine	Decreased Lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ Lamotrigine	Addition of carbamazepine decreases Lamotrigine concentration approximately 40%.
Carbamazepine (CBZ) and CBZ epoxide	? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ Lamotrigine	Decreased Lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ Lamotrigine	Decreased Lamotrigine concentration approximately 40%.
Rifampin	↓ Lamotrigine	Decreased Lamotrigine AUC approximately 40%.
Valproate	↑ Lamotrigine	Increased Lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

Table name:

Bleeding times
Clinical Impact:	Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention:	This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact:	The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention:	Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact:	Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention:	This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.12, 7.3)

Table name:

Table 4: Summary of AED Interactions with Topiramate
AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a b.i.d. dosing regimen of phenytoin	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxideIs not administered but is an active metabolite of carbamazepine	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	15% increase
NC = Less than 10% change in plasma concentration AED = Antiepileptic drug NE = Not Evaluated TPM = Topiramate

Table name:

Drugs that Affect Renal Function	A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics	Dofetilide	Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
	Sotalol	Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
	Dronedarone	Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog	Teriparatide	Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement	Thyroid Supplement	Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics	Epinephrine Norepinephrine Dopamine	Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents	Succinylcholine	May cause sudden extrusion of potassium from muscle cells causing arrhythmias inpatients taking digoxin.
Supplements	Calcium	If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers		Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.
Hyperpolarization-activated cyclic nucleotide-gated channel blocker	Ivabradine	Can increase the risk of bradycardia.

Table name:

Table 2: Clinically Significant Drug Interactions with Tramadol Hydrochloride Extended-Release Tablets
Inhibitors of CYP2D6
Clinical Impact :	The concomitant use of tramadol hydrochloride extended-release tablets and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride extended-release tablets is achieved. Since M1 is a more potent µ-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease and the M1 plasma concentration will increase which could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, and may cause potentially fatal respiratory depression [ see Clinical Pharmacology ( 12 . 3)].
Intervention :	If concomitant use of a CYP2D6 inhibitor is necessary, follow patients closely for adverse reactions including opioid withdrawal, seizures, and serotonin syndrome. If a CYP2D6 inhibitor is discontinued, consider lowering tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved. Follow patients closely for adverse events including respiratory depression and sedation.
Examples	Quinidine, fluoxetine, paroxetine and bupropion
Inhibitors of CYP3A4
Clinical Impact :	The concomitant use of tramadol hydrochloride extended-release tablets and CYP3A4 inhibitors can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1. Follow patients closely for increased risk of serious adverse events including seizures and serotonin syndrome, and adverse reactions related to opioid toxicity including potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride extended-release tablets is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease [ see Clinical Pharmacology ( 12 . 3)], resulting in decreased opioid efficacy and possibly signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol.
Intervention :	If concomitant use is necessary, consider dosage reduction of tramadol hydrochloride extended-release tablets until stable drug effects are achieved. Follow patients closely for seizures and serotonin syndrome, and signs of respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved and follow patients for signs and symptoms of opioid withdrawal.
Examples	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact :	The concomitant use of tramadol hydrochloride extended-release tablets and CYP3A4 inducers can decrease the plasma concentration of tramadol [ see Clinical Pharmacology ( 12 . 3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol, [ see Warnings and Precautions ( 5 . 4)]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase [ see Clinical Pharmacology ( 12 . 3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause seizures and serotonin syndrome, and potentially fatal respiratory depression.
Intervention :	If concomitant use is necessary, consider increasing the tramadol hydrochloride extended-release tablets dosage until stable drug effects are achieved. Follow patients for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider tramadol hydrochloride extended-release tablets dosage reduction and monitor for seizures and serotonin syndrome, and signs of sedation and respiratory depression. Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of tramadol hydrochloride extended-release tablets and carbamazepine is not recommended.
Examples :	Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System ( CNS ) Depressants
Clinical Impact :	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention :	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [ see Warnings and Precautions ( 5 . 5)].
Examples :	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact :	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention :	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue tramadol hydrochloride extended-release tablets if serotonin syndrome is suspected.
Examples :	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors ( MAOIs )
Clinical Impact :	MAOI interactions with opioids may manifest as serotonin syndrome [ see Warnings and Precautions ( 5 . 6 )] or opioid toxicity (e.g., respiratory depression, coma) [ see Warnings and Precautions ( 5 . 2)].
Intervention :	Do not use tramadol hydrochloride extended-release tablets in patients taking MAOIs or within 14 days of stopping such treatment.
Examples :	phenelzine, tranylcypromine, linezolid
Mixed Agonist / Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact :	May reduce the analgesic effect of tramadol hydrochloride extended-release tablets and/or precipitate withdrawal symptoms.
Intervention :	Avoid concomitant use.
Examples :	butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact :	Tramadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention :	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of tramadol hydrochloride extended-release tablets and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact :	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention :	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact :	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention :	Monitor patients for signs of urinary retention or reduced gastric motility when tramadol hydrochloride extended-release tablets are used concomitantly with anticholinergic drugs.
Digoxin
Clinical Impact :	Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity.
Intervention :	Follow patients for signs of digoxin toxicity and adjust the dosage of digoxin as needed.
Warfarin
Clinical Impact :	Post-marketing surveillance of tramadol has revealed rare reports of alteration of warfarin effect, including elevation of prothrombin times.
Intervention :	Monitor the prothrombin time of patients on warfarin for signs of an interaction and adjust the dosage of warfarin as needed.

Table name: ContraindicatedAvoid UseUse with cautionUse with cautionUse with caution


Drugs That are Affected by CIPRO
Drug(s)	Recommendation	Comments
Tizanidine
Concomitant administration of tizanidine and CIPRO is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)]
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of CIPRO with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.9)].
Drugs Known to Prolong QT Interval
CIPRO may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.11) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when CIPRO and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when CIPRO is co-administered with oral antidiabetic drugs [see Adverse Reactions (6.1)].
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon CIPRO discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of CIPRO with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when CIPRO is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of CIPRO to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of CIPRO with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant CIPRO therapy is indicated.
Ropinirole
Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with CIPRO [see Warnings and Precautions (5.16)].
Clozapine
Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with CIPRO are advised.
NSAIDs
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution Two-fold increase in exposure	Monitor for sildenafil toxicity [see Clinical Pharmacology (12.3 )].
Duloxetine	Avoid Use Five-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	CIPRO inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of CIPRO
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx^® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	CIPRO should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2.4)].	Decrease CIPRO absorption, resulting in lower serum and urine levels
Probenecid	Use with caution (interferes with renal tubular secretion of CIPRO and increases CIPRO serum levels)	Potentiation of CIPRO toxicity may occur.

Table name:

Drugs That Interfere with Hemostasis
Clinical Impact:	Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of indomethacin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions ( 5.11 )].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions ( 5.2 ) ].
Intervention:	Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions ( 5.11 )].Indomethacin is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of indomethacin capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.During concomitant use of indomethacin capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions ( 5.6 )].When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.It has been reported that the addition of triamterene to a maintenance schedule of Indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together.Both indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently [ see Warnings and Precautions ( 5.6 )].
Intervention:	Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels. [ see Warnings and Precautions ( 5.6 )].
Digoxin
Clinical Impact:	The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention:	During concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions ( 5.2 )]. Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin [see Clinical Pharmacology ( 12.3 )].In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage.
Intervention:	The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Probenecid
Clinical Impact:	When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased.
Intervention:	During the concomitant use of indomethacin and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments.

Table name:

Antiarrhythmics	Dofetilide	Concomitant administration with digoxin was associated with a higher rate of torsades de pointes.
	Moricizine	Reported to increase PR interval and QRS duration. There are reports of first degree atrioventricular block or bundle branch block developing with digitalis administration. The known effects of moricizine on calcium conductance may explain the effects on atrioventricular node conduction.
	Sotalol	Proarrhythmic events even more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving dioxin.
Parathyroid Hormone Analog	Teriparatide	Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid Supplement	Thyroid	Treatment of hyperthyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics	Epinepherine	Can increase the risk of cardiac arrhythmias.
	Norepinephrine
	Dopamine
Neuromuscular Blocking Agents	Succinylcholine	May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements	Calcium	If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers	Additive effects on AV node conduction can result in complete heart block.

Table name:

AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NCor25%increase^a	48%decrease
Carbamazepine(CBZ)	NC	40%decrease
CBZepoxide^b	NC	NE
Valproic acid	11%decrease	14%decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NCatTPM dosesupto400 mg/day	13%decrease

Table name:

Bleeding times
Clinical Impact:	Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention:	This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact:	The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention:	Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact:	Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention:	This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.

Table 5: Established Drug Interactions Based on Studies with Didanosine Delayed-Release Capsules or Studies with Buffered Formulations of Didanosine and Expected to Occur with Didanosine Delayed-Release Capsules
Drug	Effect	Clinical Comment
ganciclovir	↑didanosine concentration	If there is no suitable alternative to ganciclovir, then use in combination with didanosine delayed-release capsules with caution. Monitor for didanosine-associated toxicity.
methadone	↓didanosine concentration	If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is didanosine delayed-release capsules. Patients should be closely monitored for adequate clinical response when didanosine delayed-release capsules are coadministered with methadone, including monitoring for changes in HIV RNA viral load. Do not coadminister methadone with didanosine pediatric powder due to significant decreases in didanosine concentrations.
nelfinavir	No interaction 1 hour after didanosine	Administer nelfinavir 1 hour after didanosine delayed-release capsules.
tenofovir disoproxil fumarate	↑didanosine concentration	A dose reduction of didanosine delayed-release capsules to the following dosage once daily taken together with tenofovir disoproxil fumarate and a light meal (400 kcalories or less and 20% fat or less) or in the fasted state is recommended.Coadministration of didanosine with food decreases didanosine concentrations. Thus, although not studied, it is possible that coadministration with heavier meals could reduce didanosine concentrations further.
↑ Indicates increase. ↓ Indicates decrease.

Table name:

Table 1: Clinically Significant Drug Interactions with Naproxen
Drugs That Interfere with Hemostasis
Clinical Impact:	Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of naproxen tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	Concomitant use of naproxen tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen tablets are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of naproxen tablets and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of naproxen tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention	During concomitant use of naproxen tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of naproxen tablets and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen tablets and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen tablets and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen tablets and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen tablets and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen tablets and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of naproxen tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen tablets are not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen tablets are not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxen tablets are not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen tablets and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:	Patients simultaneously receiving naproxen tablets and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

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Table 5 Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours in healthy adult subjects (n=24)
Concomitant Drug	CmaxSS (Peak plasma concentration)	AUCss(0-12h) (Extent of systemic exposure)
Erythromycin (500 mg every 8 hrs)	+82%	+109%
Ketoconazole (400 mg once daily)	+135%	+164%

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 4. Selected Drugs that are contraindicated for use with itraconazoleThis list is not all-inclusive.
Antipsychotics	pimozide
Antiarrhythmics	dofetilide, quinidine
Benzodiazepines	oral midazolamFor information on parenterally administered midazolam, see the Benzodiazepine paragraph below., triazolam
Calcium Channel Blockers	Nisoldipine, felodipine
Ergot Alkaloids	dihydroergotamine, ergotamine, ergometrine (ergonovine), methylergometrine (methylergonovine)
Gastrointestinal Motility Agents	cisapride
HMG CoA-Reductase Inhibitors	lovastatin, simvastatin
Opiate Analgesics	levacetylmethadol (levomethadyl), methadone

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Table 2: Drug-Thyroidal Axis Interactions
	Drug or Drug Class		Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
		Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
		Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
		Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
		Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
		Amiodarone Iodide (including iodine- containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
	Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
	Drugs that may increase		Drugs that may decrease
	serum TBG concentration		serum TBG concentration
	Clofibrate		Androgens / Anabolic Steroids
	Estrogen-containing oral		Asparaginase
	contraceptives		Glucocorticoids
	Estrogens (oral)		Slow-Release Nicotinic Acid
	Heroin / Methadone
	5-Fluorouracil
	Mitotane
	Tamoxifen
	Drugs that may cause protein-binding site displacement
	Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)		Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
	Carbamazepine Hydantoins Phenobarbital Rifampin		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
	Drugs that may decrease T ₄ 5' - deiodinase activity
	Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)		Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, Ieading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
	Miscellaneous
	Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives		Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
	Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
	Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin		Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
	Cardiac Glycosides		Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
	Cytokines - Interferon-α - Interleukin-2		Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
	Growth Hormones - Somatrem - Somatropin		Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
	Ketamine		Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
	Methylxanthine Bronchodilators - (e.g., Theophylline)		Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
	Radiographic Agents		Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
	Sympathomimetics		Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
	Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics		These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
↓= Decreased (induces lamotrigine gluronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ?= Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
	? CBZ epoxide	May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 4: Clinically Important Drug Interactions with VIIBRYD
Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Monoamine Oxidase Inhibitors (MAOIs)	The concomitant use of MAOIs and serotonergic drugs including VIIBRYD increases the risk of serotonin syndrome.	VIIBRYD is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Contraindications (4), Dosage and Administration (2.3), and Warnings and Precautions (5.2)].
Other Serotonergic Drugs	The concomitant use of serotonergic drugs including VIIBRYD and other serotonergic drugs increases the risk of serotonin syndrome.	Monitor patients for signs and symptoms of serotonin syndrome, particularly during VIIBRYD initiation. If serotonin syndrome occurs, consider discontinuation of VIIBRYD and/or concomitant serotonergic drugs [see Warnings and Precautions (5.2)].
Antiplatelet Agents and Anticoagulants	Serotonin release by platelets plays an important role in hemostasis. The concurrent use of an antiplatelet agent or anticoagulant with VIIBRYD may potentiate the risk of bleeding.	Inform patients of the increased risk of bleeding with the concomitant use of VIIBRYD and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio (INR) when initiating or discontinuing VIIBRYD [see Warnings and Precautions (5.3)].
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin, voriconazole)	The concomitant use of VIIBRYD and strong CYP3A4 inhibitors increased the exposure of vilazodone compared to the use of VIIBRYD alone [see Clinical Pharmacology (12.3)].	The VIIBRYD dose should not exceed 20 mg once daily with the concomitant use of a strong CYP3A4 inhibitor [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].
Strong CYP3A4 Inducers (e.g., carbamazepine, phenytoin, rifampin)	The concomitant use of VIIBRYD and strong CYP3A4 inducers decreased the exposure of vilazodone compared to the use of VIIBRYD alone [see Clinical Pharmacology (12.3)].	Based on clinical response, consider increasing the dosage of VIIBRYD, over 1 to 2 weeks in patients taking strong CYP3A4 inducers for greater than 14 days [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].
Digoxin	Digoxin is a narrow therapeutic index drug. Concomitant use of VIIBRYD increased digoxin concentrations [see Clinical Pharmacology (12.3)].	Measure serum digoxin concentrations before initiating concomitant use of VIIBRYD. Continue monitoring and reduce digoxin dose as necessary.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T ₄ and T ₃levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT ₄ . Continued administration results in a decrease in serum T ₄ and normal FT ₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T ₄ and T ₃ to TBG and transthyretin. An initial increase in serum FT ₄ is followed by return of FT ₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T ₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T ₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T ₄ to T ₃, leading to decreased T ₃ levels. However, serum T ₄levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T ₃ and T ₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T ₃concentrations by 30% with minimal change in serum T ₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T ₃ and T ₄levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³ I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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I. Due to the competition of salicylate with other drugs for binding to serum albumin the following drug interactions may occur:
DRUG	DESCRIPTION OF INTERACTION
Sulfonylureas	Hypoglycemia potentiated.
Methotrexate	Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants	Increased bleeding.
II. Drugs changing salicylate levels by altering renal tubular reabsorption:
DRUG	DESCRIPTION OF INTERACTION
Corticosteroids	Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents	Increases plasma salicylate levels.
Alkanizing Agents	Decreased plasma salicylate levels.
III. Drugs with complicated interactions with salicylates:
DRUG	DESCRIPTION OF INTERACTION
Heparin	Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients.
Pyrazinamide	Inhibits pyrazinamide-induced hyperuricemia.
Uricosuric Agents	Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.
The following alterations of laboratory tests have been reported during salicylate therapy:
LABORATORY TESTS	EFFECT OF SALICYLATES
Thyroid Function	Decreased PBI; increased t₃ uptake.
Urinary Sugar	False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.).
5-Hydroxyindole acetic acid	False negative with fluorometric test.
Acetone ketone bodies	False positive FeCI₃ in Gerhardt reaction; red color persists with boiling.
17-OH corticosteroids	False reduced values with >4.8g q.d. salicylate.
Vanilmandelic acid	False reduced values.
Uric Acid	May increase or decrease depending on dose.
Prothrombin	Decreased levels; slightly increased prothrombin time.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir )	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Interacting DrugInteracting Drug	InteractionInteraction
Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.12, 7.3)

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine, danazol	Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem	Do not exceed 40 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Table 3: Clinically Relevant Interactions Affecting Drugs Co-Administered with Omeprazole and Interaction with Diagnostics
Antiretrovirals
Clinical Impact:	The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology ( 12.3)]. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)]. There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
Intervention:	Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications ( 4)] . Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:	Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention:	Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact:	Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions ( 5.11)].
Intervention:	A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact:	Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology ( 12.3)]. There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel .
Intervention:	Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions ( 5.6)].
Citalopram
Clinical Impact:	Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology ( 12.3)] .
Intervention:	Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:	Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology ( 12.3)].
Intervention:	Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:	Potential for increased exposure of phenytoin.
Intervention:	Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:	Increased exposure of diazepam [see Clinical Pharmacology ( 12.3)] .
Intervention:	Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:	Potential for increased exposure of digoxin [see Clinical Pharmacology ( 12.3)].
Intervention:	Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:	Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:	Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology ( 12.3)] . See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:	Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:	See Contraindications, Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact:	Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19 .
Intervention:	Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:	Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions ( 5.10), Clinical Pharmacology ( 12.2)] .
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:	Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology ( 12.2)] .
False Positive Urine Tests for THC
Clinical Impact:	There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:	An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:	There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:	Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.

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*Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	Cmax
Enzyme (CYP2D6) inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not Needed

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Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio Change relative to reference )		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Drugs That Interfere with Hemostasis
Clinical Impact:	• Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	• During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Do not co-administer the intravenous formulation in the same IV line with an multivalent cation, e.g., magnesium (2.4 , 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.12 , 7.3)

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Table 25: Clinically Important Drug Interactions with ABILIFY:
Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of ABILIFY with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of ABILIFY alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of ABILIFY with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the ABILIFY dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of ABILIFY and carbamazepine decreased the exposure of aripiprazole compared to the use of ABILIFY alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of ABILIFY with a strong CYP3A4 inducer, consider increasing the ABILIFY dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.7)].
Benzodiazepines (e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.7)]	Monitor sedation and blood pressure. Adjust dose accordingly.

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Table 2Clinically Significant Drug Interactions with Indomethacin Drugs That Interfere with Hemostasis
Clinical Impact :	Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant uses of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention :	Monitor patients with concomitant use of indomethacin capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions ( 5 . 11)].
Aspirin
Clinical Impact :	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions ( 5 . 2)].
Intervention :	Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions ( 5 . 11)]. Indomethacin capsules are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors , Angiotensin Receptor Blockers , and Beta - Blockers
Clinical Impact :	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention :	During concomitant use of indomethacin capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of Indomethacin capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions ( 5 . 6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact :	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. It has been reported that the addition of triamterene to a maintenance schedule of Indomethacin capsules resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin capsules and triamterene should not be administered together. Both Indomethacin capsules and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin capsules and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently.
Intervention :	Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels [see Warnings and Precautions ( 5 . 6)].
Digoxin
Clinical Impact :	The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention :	During concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact :	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention :	During concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact :	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention :	During concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact :	Concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention :	During concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact :	Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions ( 5 . 2 )]. Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin. [see Clinical Pharmacology ( 12 . 3)]. In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage.
Intervention :	The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended.
Pemetrexed
Clinical Impact :	Concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention :	During concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Probenecid
Clinical Impact :	When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased.
Intervention :	During the concomitant use of indomethacin capsules and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments.

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Drug Name	Effect on Concentration of Nevirapine or Concomitant Drug	Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir*	↓ Atazanavir ↑ Nevirapine	Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir*	↓ Amprenavir ↑ Nevirapine	Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir*	↓ Amprenavir ↑ Nevirapine	No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir*	↓ Indinavir	The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir*	↓ Lopinavir	Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir*	↓ Nelfinavir M8 Metabolite ↓ Nelfinavir C_min	The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/ritonavir	The interaction between nevirapine and saquinavir/ritonavir has not been evaluated.	The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz*	↓ Efavirenz	The appropriate doses of these combinations with respect to safety and efficacy have not been established.
Delavirdine Etravirine Rilpivirine		Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.
Hepatitis C Antiviral Agents
Boceprevir	Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine.	Nevirapine and boceprevir should not be coadministered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy.
Telaprevir	Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir.	Nevirapine and telaprevir should not be coadministered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events.
Other Agents
Analgesics: Methadone*	↓ Methadone	Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics: Amiodarone, disopyramide, lidocaine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Antibiotics: Clarithromycin*	↓ Clarithromycin ↑ 14-OH clarithromycin	Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Rifabutin*	↑ Rifabutin	Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin*	↓ Nevirapine	Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants: Carbamazepine, clonazepam, ethosuximide	Plasma concentrations of nevirapine and the anticonvulsant may be decreased.	Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals: Fluconazole*	↑ Nevirapine	Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Ketoconazole*	↓ Ketoconazole	Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Itraconazole	↓ Itraconazole	Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics: Warfarin	Plasma concentrations may be increased.	Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers: Diltiazem, nifedipine, verapamil	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Cancer chemotherapy: Cyclophosphamide	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Ergot alkaloids: Ergotamine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Motility agents: Cisapride	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Opiate agonists: Fentanyl	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Oral contraceptives: Ethinyl estradiol and Norethindrone*	↓ Ethinyl estradiol ↓ Norethindrone	Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.

Table name:

Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin	Monitor phenytoin level (7)
Methotrexate	Monitor for methotrexate toxicity (7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine (7)

Table name:

Table 4: Drugs Having Clinically Important Interactions with Amphetamines
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact	Concomitant use of MAOIs and CNS stimulants can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure.
Intervention	Do not administer MAS-ER Capsules concomitantly or within 14 days after discontinuing MAOI [see CONTRAINDICATIONS (4) and WARNINGS AND PRECAUTIONS (5.6)].
Examples	selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
Serotonergic Drugs
Clinical Impact	The concomitant use of MAS-ER Capsules and serotonergic drugs increases the risk of serotonin syndrome.
Intervention	Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome, particularly during MAS-ER Capsules initiation or dosage increase. If serotonin syndrome occurs, discontinue MAS-ER Capsules and the concomitant serotonergic drug(s) [see WARNINGS AND PRECAUTIONS (5.6)].
Examples	selective serotonin reuptake inhibitors (SSRI), serotonin norepinephrine reuptake inhibitors (SNRI), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John's Wort
CYP2D6 Inhibitors
Clinical Impact	The concomitant use of MAS-ER Capsules and CYP2D6 inhibitors may increase the exposure of MAS-ER Capsules compared to the use of the drug alone and increase the risk of serotonin syndrome.
Intervention	Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome particularly during MAS-ER Capsules initiation and after a dosage increase. If serotonin syndrome occurs, discontinue MAS-ER Capsules and the CYP2D6 inhibitor [see WARNINGS AND PRECAUTIONS (5.6) and OVERDOSAGE (10)].
Examples	paroxetine and fluoxetine (also serotonergic drugs), quinidine, ritonavir
Alkalinizing Agents
Clinical Impact	Increase blood levels and potentiate the action of amphetamine.
Intervention	Co-administration of MAS-ER Capsules and gastrointestinal or urinary alkalinizing agents should be avoided.
Examples	Gastrointestinal alkalinizing agents (e.g., sodium bicarbonate). Urinary alkalinizing agents (e.g. acetazolamide, some thiazides).
Acidifying Agents
Clinical Impact	Lower blood levels and efficacy of amphetamines.
Intervention	Increase dose based on clinical response.
Examples	Gastrointestinal acidifying agents (e.g., guanethidine, reserpine, glutamic acid HCl, ascorbic acid). Urinary acidifying agents (e.g., ammonium chloride, sodium acid phosphate, methenamine salts).
Tricyclic Antidepressants
Clinical Impact	May enhance the activity of tricyclic or sympathomimetic agents causing striking and sustained increases in the concentration of d-amphetamine in the brain; cardiovascular effects can be potentiated.
Intervention	Monitor frequently and adjust or use alternative therapy based on clinical response.
Examples	desipramine, protriptyline
Proton Pump Inhibitors
Clinical Impact	Time to maximum concentration (Tmax) of amphetamine is decreased compared to when administered alone.
Intervention	Monitor patients for changes in clinical effect and adjust therapy based on clinical response.
Examples	omeprazole

Table name:

Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ Lamotrigine	Decreased Lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ Lamotrigine	Addition of carbamazepine decreases Lamotrigine concentration approximately 40%.
Carbamazepine (CBZ) and CBZ epoxide	? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ Lamotrigine	Decreased Lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ Lamotrigine	Decreased Lamotrigine concentration approximately 40%.
Rifampin	↓ Lamotrigine	Decreased Lamotrigine AUC approximately 40%.
Valproate	↑ Lamotrigine	Increased Lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

Table name:

Table 2: Clinically Significant Drug Interactions with OPANA Injection
Benzodiazepines and other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue OPANA injection if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)]. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Intervention:	The use of OPANA injection is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of OPANA injection and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine,
Muscle Relaxants
Clinical Impact:	Oxymorphone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of OPANA ER and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when OPANA is used concomitantly with anticholinergic drugs.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when OPANA injection is used concomitantly with anticholinergic drugs.
Cimetidine
Clinical Impact:	Cimetidine can potentiate opioid-induced respiratory depression.
Intervention:	Monitor patients for respiratory depression when OPANA ER and cimetidine are used concurrently.
Propofol
Clinical Impact:	Incidence of bradycardia was increased when oxymorphone was combined with propofol for induction of anesthesia
Intervention:	Do not use concurrently with Propofol.

Table name:

Table 3: Clinically Significant Drug Interactions with Ibuprofen
Drugs That Interfere with Hemostasis
Clinical Impact:	Ibuprofen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of ibuprofen and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of CALDOLOR with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention:	Concomitant use of CALDOLOR and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. CALDOLOR is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of CALDOLOR and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of CALDOLOR and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of CALDOLOR with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact:	The concomitant use of ibuprofen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of CADOLOR and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of CALDOLOR and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of CALDOLOR and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of CALDOLOR and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention:	During concomitant use of CALDOLOR and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of ibuprofen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention:	The concomitant use of ibuprofen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of CALDOLOR and pemetrexed, may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of CALDOLOR and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.

Table name:

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir )	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)	Do not exceed 40 mg atorvastatin daily

Table name:

Effects on steady-state fexofenadine pharmacokinetics after 7 days of co-administration with fexofenadine hydrochloride 120 mg every 12 hours (two times the recommended twice daily dose) in healthy volunteers (n=24)
Concomitant Drug	C_maxSS (Peak plasma concentration)	AUC_ss(0–12h) (Extent of systemic exposure)
Erythromycin (500 mg every 8 hrs)	+82%	+109%
Ketoconazole (400 mg once daily)	+135%	+164%

Table name:

Table 6: Effect of VYVANSE on Other Drugs
Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Monoamine Oxidase Inhibitors (MAOIs)	Concomitant use of MAOIs and CNS stimulants can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure.	Do not administer VYVANSE concomitantly or within 14 days after discontinuing MAOI treatment [see Contraindications (4)]

Table name:

Table 2 Rifabutin Interaction Studies
Coadministered drug	Dosing regimen of coadministered drug	Dosing regimen of rifabutin	Study population (n)	Effect on rifabutin	Effect on coadministered drug	Recommendation
↑ indicates increase; ↓ indicates decrease; ↔ indicates no significant change
QD- once daily; BID- twice daily; TID – thrice daily
ND - No Data
AUC - Area under the Concentration vs. Time Curve; C_max - Maximum serum concentration
ANTIVIRALS
Amprenavir	1200 mg BID × 10 days	300 mg QD × 10 days	Healthy male subjects (6)	↑ AUC by 193%, ↑ Cmax by 119%	↔	Reduce rifabutin dose by at least 50%. Monitor closely for adverse reactions.
Delavirdine	400 mg TID	300 mg QD	HIV-infected patients (7)	↑ AUC by 230%, ↑ Cmax by 128%	↓ AUC by 80%, ↓ Cmax by 75%, ↓ Cmin by 17%	CONTRAINDICATED
Didanosine	167 or 250 mg BID × 12 days	300 or 600 mg QD × 1	HIV-infected patients (11)	↔	↔
Fosamprenavir/ ritonavir	700 mg BID plus ritonavir 100 mg BID × 2 weeks	150 mg every other day × 2 weeks	Healthy subjects (15)	↔ AUCcompared to rifabutin 300 mg QD alone ↓ Cmax by 15%	↑ AUC by 35%compared to historical control (fosamprenavir/ritonavir 700/100 mg BID), ↑ Cmax by 36%, ↑ Cmin by 36%,	Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with fosamprenavir/ritonavir combination.
Indinavir	800 mg TID × 10 days	300 mg QD × 10 days	Healthy subjects (10)	↑ AUC by 173%, ↑ Cmax by 134%	↓ AUC by 34%, ↓ Cmax by 25%, ↓ Cmin by 39%	Reduce rifabutin dose by 50%, and increase indinavir dose from 800 mg to 1000 mg TID.
Lopinavir/ ritonavir	400/100 mg BID × 20 days	150 mg QD × 10 days	Healthy subjects (14)	↑ AUC by 203% also taking zidovudine 500 mg QD ↓ Cmax by 112%	↔	Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed.
Saquinavir/ ritonavir	1000/100 mg BID × 14 or 22 days	150 mg every 3 days × 21–22 days	Healthy subjects	↑ AUC by 53% compared to rifabutin 150 mg QD alone ↑ Cmax by 88% (n=11)	↓ AUC by 13%, ↓ Cmax by 15%, (n=19)	Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with saquinavir/ritonavir combination. Monitor closely for adverse reactions.
Ritonavir	500 mg BID × 10 days	150 mg QD × 16 days	Healthy subjects (5)	↑ AUC by 300%, ↑ Cmax by 150%	ND	Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed.
Tipranavir/ ritonavir	500/200 BID × 15 doses	150 mg single dose	Healthy subjects (20)	↑ AUC by 190%, ↑ Cmax by 70%	↔	Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with tipranavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed.
Nelfinavir	1250 mg BID × 7–8 days	150 mg QD × 8 days	HIV-infected patients (11)	↑ AUC by 83%, compared to rifabutin 300 mg QD alone ↑ Cmax by 19%	↔	Reduce rifabutin dose by 50% (to 150 mg QD) and increase the nelfinavir dose to 1250 mg BID
Zidovudine	100 or 200 mg q4h	300 or 450 mg QD	HIV-infected patients (16)	↔	↓ AUC by 32%, ↓ Cmax by 48%,	Because zidovudine levels remained within the therapeutic range during coadministration of rifabutin, dosage adjustments are not necessary.
ANTIFUNGALS
Fluconazole	200 mg QD × 2 weeks	300 mg QD × 2 weeks	HIV-infected patients (12)	↑ AUC by 82%, ↑ Cmax by 88%	↔	Monitor for rifabutin associated adverse events. Reduce rifabutin dose or suspend rifabutin use if toxicity is suspected.
Posaconazole	200 mg QD × 10 days	300 mg QD × 17 days	Healthy subjects (8)	↑ AUC by 72%, ↑ Cmax by 31%	↓ AUC by 49%, ↓ Cmax by 43%	If co-administration of these two drugs cannot be avoided, patients should be monitored for adverse events associated with rifabutin administration, and lack of posaconazole efficacy.
Itraconazole	200 mg QD	300 mg QD	HIV-Infected patients (6)	↑data from a case report	↓ AUC by 70%, ↓ Cmax by 75%,	If co-administration of these two drugs cannot be avoided, patients should be monitored for adverse events associated with rifabutin administration, and lack of itraconazole efficacy. In a separate study, one case of uveitis was associated with increased serum rifabutin levels following co-administration of rifabutin (300 mg QD) with itraconazole (600–900 mg QD).
Voriconazole	400 mg BID × 7 days (maintenance dose)	300 mg QD × 7 days	Healthy male subjects (12)	↑ AUC by 331%, ↑ Cmax by 195%	↑ AUC by ~100%, ↑ Cmax by ~100%compared to voriconazole 200 mg BID alone	CONTRAINDICATED
ANTI-PCP (Pneumocystis carinii pneumonia)
Dapsone	50 mg QD	300 mg QD	HIV-infected patients (16)	ND	↓ AUC by 27 –40%
Sulfamethoxazole-Trimethoprim	800/160 mg	300 mg QD	HIV-infected patients (12)	↔	↓ AUC by 15–20%
ANTI-MAC (Mycobacterium avium intracellulare complex)
Azithromycin	500 mg QD × 1 day, then 250 mg QD × 9 days	300 mg QD	Healthy subjects (6)	↔	↔
Clarithromycin	500 mg BID	300 mg QD	HIV-infected patients (12)	↑ AUC by 75%	↓ AUC by 50%	Monitor for rifabutin associated adverse events. Reduce dose or suspend use of rifabutin if toxicity is suspected. Alternative treatment for clarithromycin should be considered when treating patients receiving rifabutin
ANTI-TB (Tuberculosis)
Ethambutol	1200 mg	300 mg QD × 7 days	Healthy subjects (10)	ND	↔
Isoniazid	300 mg	300 mg QD × 7 days	Healthy subjects (6)	ND	↔
OTHER
Methadone	20 – 100 mg QD	300 mg QD × 13 days	HIV-infected patients (24)	ND	↔
Ethinylestradiol (EE)/ Norethindrone (NE)	35 mg EE / 1 mg NE × 21 days	300 mg QD × 10 days	Healthy female subjects (22)	ND	EE: ↓ AUC by 35%, ↓ C_max by 20% NE: ↓ AUC by 46%	Patients should be advised to use additional or alternative methods of contraception.
Theophylline	5 mg/kg	300 mg × 14 days	Healthy subjects (11)	ND	↔

Table name: For patients with CL_CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CL_CR <30 mL/min the dose of clarithromycin should be reduced by 75%.

Table 7. Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class: Drug Name	Effect on Concentration of Delavirdine or Concomitant Drug	Clinical Comment
HIV-Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitor
Didanosine^a	↓Delavirdine ↓Didanosine	Administration of didanosine (buffered tablets) and RESCRIPTOR should be separated by at least 1 hour.
HIV-Antiviral Agents: Non-nucleoside Reverse Transcriptase Inhibitors
NNRTI	↔Delavirdine ↑NNRTI	Combining NNRTIs has not been shown to be beneficial. RESCRIPTOR should not be coadministered with another NNRTI.
HIV-Antiviral Agents: Protease Inhibitors
Indinavir^a	↑Indinavir	A dose reduction of indinavir to 600 mg 3 times daily should be considered when RESCRIPTOR and indinavir are coadministered.
Lopinavir/Ritonavir	↑Lopinavir ↑Ritonavir	Appropriate doses of this combination with respect to safety, efficacy, and pharmacokinetics have not been established.
Nelfinavir^a	↑Nelfinavir ↓Delavirdine	Appropriate doses of this combination with respect to safety, efficacy, and pharmacokinetics have not been established (see CLINICAL PHARMACOLOGY: Tables 1 and 2).
Ritonavir	↑Ritonavir	Appropriate doses of this combination with respect to safety, efficacy, and pharmacokinetics have not been established.
Saquinavir^a	↑Saquinavir	A dose reduction of saquinavir (soft gelatin capsules) may be considered when RESCRIPTOR and saquinavir are coadministered (see CLINICAL PHARMACOLOGY: Table 1). Appropriate doses with respect to safety, efficacy, and pharmacokinetics have not been established.
HIV-Antiviral Agents: CCR5 Inhibitor
Maraviroc	↑Maraviroc	Concomitant use of RESCRIPTOR and maraviroc has not been studied. However, RESCRIPTOR is a potent CYP3A4 inhibitor and the maraviroc dose should be reduced during coadministration. Refer to the full prescribing information for maraviroc (SELZENTRY) for dosing recommendations.
Other Agents
Acid blockers: Antacids^a	↓Delavirdine	Doses of an antacid and RESCRIPTOR should be separated by at least 1 hour, because the absorption of delavirdine is reduced when coadministered with antacids.
Histamine H₂-receptor antagonists: Cimetidine, famotidine, nizatidine, ranitidine	↓Delavirdine	These agents increase gastric pH and may reduce the absorption of delavirdine. Although the effect of these drugs on delavirdine absorption has not been evaluated, chronic use of these drugs with RESCRIPTOR is not recommended.
Proton pump inhibitors: Omeprazole, lansoprazole	↓Delavirdine	These agents increase gastric pH and may reduce the absorption of delavirdine. Although the effect of these drugs on delavirdine absorption has not been evaluated, chronic use of these drugs with RESCRIPTOR is not recommended.
Amphetamines	↑Amphetamines	Use with caution.
Antidepressant: Trazodone	↑Trazodone	Concomitant use of trazodone and RESCRIPTOR may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as RESCRIPTOR, the combination should be used with caution and a lower dose of trazodone should be considered.
Antiarrhythmics: Bepridil	↑Antiarrhythmics	Use with caution. Increased bepridil exposure may be associated with life‑threatening reactions such as cardiac arrhythmias.
Amiodarone, lidocaine (systemic), quinidine, flecainide, propafenone		Caution is warranted and therapeutic concentration monitoring is recommended, if available, for antiarrhythmics when coadministered with RESCRIPTOR.
Anticoagulant: Warfarin	↑Warfarin	It is recommended that INR (international normalized ratio) be monitored.
Anti-infective: Clarithromycin^a	↑Clarithromycin	When coadministered with RESCRIPTOR, clarithromycin should be adjusted in patients with impaired renal function:
Calcium channel blockers: Amlodipine, diltiazem, felodipine, isradipine, nifedipine, nicardipine, nimodipine, nisoldipine, verapamil	↑Calcium channel blockers	Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid: Dexamethasone	↓Delavirdine	Use with caution. RESCRIPTOR may be less effective due to decreased delavirdine plasma concentrations in patients taking these agents concomitantly.
Erectile dysfunction agents: Sildenafil	↑Sildenafil	Sildenafil should not exceed a maximum single dose of 25 mg in a 48‑hour period.
HMG-CoA reductase inhibitors: Atorvastatin, cerivastatin, fluvastatin	↑Atorvastatin ↑Cerivastatin ↑Fluvastatin	Use lowest possible dose of atorvastatin or cerivastatin, or fluvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin in combination with RESCRIPTOR.
Immunosuppressants: Cyclosporine, tacrolimus, rapamycin	↑Immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with RESCRIPTOR.
Inhaled/nasal steroid: Fluticasone	↑Fluticasone	Concomitant use of fluticasone and RESCRIPTOR may increase plasma concentrations of fluticasone. Use with caution. Consider alternatives to fluticasone, particularly for long-term use.
Narcotic analgesic: Methadone	↑Methadone	Dosage of methadone may need to be decreased when coadministered with RESCRIPTOR.
Oral contraceptives: Ethinyl estradiol	↑Ethinyl estradiol	Concentrations of ethinyl estradiol may increase. However, the clinical significance is unknown.

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AED	Dosage of AED (mg/day)	Dosage of POTIGA (mg/day)	Influence of POTIGA on AED	Influence of AED on POTIGA	Dosage Adjustment
Carbamazepine^a,b	600-2,400	300-1,200	None	31% decrease in AUC, 23% decrease in C_max	consider an increase in dosage of POTIGA when adding carbamazepine^c
Phenytoin^a,b	120-600	300-1,200	None	34% decrease in AUC, 18% decrease in C_max	consider an increase in dosage of POTIGA when adding phenytoin^c

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine concentrations approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine and carbamazepine epoxide	? carbamazepine epoxide	May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Table 3: Summary of AED Interactions with Oxcarbazepine
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400-2000	900	ncnc denotes a mean change of less than 10%	40% decrease [CI:17% decrease, 57% decrease]
Phenobarbital	100-150	600-1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI:12% decrease, 51% decrease]
Phenytoin	250-500	600-1800 >1200-2400	nc ^, Pediatrics up to 40% increaseMean increase in adults at high Oxcarbazepine doses [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400-2800	600-1800	nc	18% decrease [CI:13% decrease, 40% decrease]

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Factors	Dosage Adjustment of Aripiprazole tablets
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
KnownCYP2D6Poor Metabolizersand strongCYP3A4 inhibitors	Administer a quarter of usualdose
StrongCYP2D6 or CYP3A4inhibitors	Administerhalf of usual dose
StrongCYP2D6andCYP3A4 inhibitors	Administer a quarter of usualdose
StrongCYP3A4inducers	Double usual doseover 1 to 2 weeks

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.12, 7.3)

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 1: Clinically Significant Drug Interactions with Naproxen
Drugs That Interfere with Hemostasis
Clinical Impact:	Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of naproxen tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	Concomitant use of naproxen tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen tablets are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of naproxen tablets and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of naproxen tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention	During concomitant use of naproxen tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of naproxen tablets and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen tablets and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen tablets and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen tablets and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen tablets and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen tablets and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of naproxen tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen tablets are not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen tablets are not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxen tablets are not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen tablets and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:	Patients simultaneously receiving naproxen tablets and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

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Table 6: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
^ Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects ^ Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects *** Non-Nucleoside Reverse Transcriptase Inhibitors
Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (C_max and AUC _τ after 200 mg q12h)	Recommendations for Voriconazole Dosage Adjustment/Comments
Rifampin^* and Rifabutin^* (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (400 mg q24h)^ (CYP450 Induction) Efavirenz (300 mg q24h)^ (CYP450 Induction)	Significantly Reduced Slight Decrease in AUC _τ	Contraindicated When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)^ (CYP450 Induction) Low-dose Ritonavir (100 mg q12h)^ (CYP450 Induction)	Significantly Reduced Reduced	Contraindicated Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Phenytoin^* (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John’s Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives^** containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole^** (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIs^*** (CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure) A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to voriconazole Careful assessment of voriconazole effectiveness

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.5, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine, danazol	Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.12, 7.3)

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin	Monitor phenytoin level (7)
Methotrexate	Monitor for methotrexate toxicity (7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine (7)

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Table 3 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology ( 12.3), Table 4 for Magnitude of Interaction.
*The interaction between Nevirapine and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.

Drug Name	Effect on Concentration of Nevirapine or Concomitant Drug	Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir*	↓ Atazanavir ↑ Nevirapine	Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir* Fosamprenavir/Ritonavir*	↓ Amprenavir ↑ Nevirapine ↓ Amprenavir ↑ Nevirapine	Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. No dosing adjustments are required when nevirapine is coadministered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir*	↓ Indinavir	The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir*	↓ Lopinavir	Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir*	↓ Nelfinavir M8 Metabolite ↓ Nelfinavir C _min	The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/Ritonavir	The interaction between Nevirapine and saquinavir/ritonavir has not been evaluated	The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz* Delavirdine Etravirine Rilpivirine	↓ Efavirenz	The appropriate doses of these combinations with respect to safety and efficacy have not been established. Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.
Hepatitis C Antiviral Agents
Boceprevir	Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine.	Nevirapine and boceprevir should not be coadministered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy.
Telaprevir	Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir.	Nevirapine and telaprevir should not be coadministered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events.
Other Agents
Analgesics: Methadone*	↓ Methadone	Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadonemaintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics: Amiodarone, disopyramide, lidocaine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Antibiotics: Clarithromycin* Rifabutin* Rifampin*	↓ Clarithromycin ↑ 14-OH clarithromycin ↑ Rifabutin ↓ Nevirapine	Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered. Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients coinfected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants: Carbamazepine, clonazepam, ethosuximide	Plasma concentrations of nevirapine and the anticonvulsant may be decreased.	Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals: Fluconazole* Ketoconazole* Itraconazole	↑ Nevirapine ↓ Ketoconazole ↓ Itraconazole	Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events. Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics: Warfarin	Plasma concentrations may be increased.	Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers: Diltiazem, nifedipine, verapamil	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Cancer chemotherapy: Cyclophosphamide	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Ergot alkaloids: Ergotamine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Motility agents: Cisapride	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Opiate agonists: Fentanyl	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Oral contraceptives: Ethinyl estradiol and Norethindrone*	↓Ethinyl estradiol ↓Norethindrone	Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.

Table name:

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

Table name:

Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.
albuterol,	famotidine	nizatidine
systemic and inhaled	felodipine	norfloxacin
amoxicillin	finasteride	ofloxacin
ampicillin,	hydrocortisone	omeprazole
with or without	isoflurane	prednisone, prednisolone
sulbactam	isoniazid	ranitidine
atenolol	isradipine	rifabutin
azithromycin	influenza vaccine	roxithromycin
caffeine,	ketoconazole	sorbitol
dietary ingestion	lomefloxacin	(purgative doses do not
cefaclor	mebendazole	inhibit theophylline
co-trimoxazole	medroxyprogesterone	absorption)
(trimethoprim and	methylprednisolone	sucralfate
sulfamethoxazole)	metronidazole	terbutaline, systemic
diltiazem	metoprolol	terfenadine
dirithromycin	nadolol	tetracycline
enflurane	nifedipine	tocainide

Table name:

Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine,danazol	Do not exceed 10 mg simvastatindaily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem	Do not exceed 40 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

Table name:

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

Table name:

Drugs that Affect Renal Function	A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrhythmics	Dofetilide	Concomitant administration with digoxin was associated with a higher rate of torsades de pointes.
	Sotalol	Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
	Dronedarone	Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog	Teriparatide	Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement	Thyroid	Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics	Epinephrine Norepinephrine Dopamine	Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents	Succinylcholine	May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements	Calcium	If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers		Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.

Table name:

Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
* Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing.
	20 mg/day	4 mg/day	1.6	-	Do not exceed 8 mg/day
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed

Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

Table name:

Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistatcontaining products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin dailyFor patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

Table name:

Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.6).]
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported . Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [see Adverse Reactions (6.1).]
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution 2-fold increase in exposure	Monitor for sildenafil toxicity (see Pharmacokinetics -(12.3)-] .
Duloxetine	Avoid Use 5-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx ^® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2)].	Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.12, 7.3)

Table name:

Table 9: Drugs That are Affected by and Affecting Ciprofloxacin Tablets
Drugs That are Affected by C iprofloxacin Tablets
Drug(s)	Recommendation		Comments
Tizanidine	Contraindicated		Concomitant administration of tizanidine and ciprofloxacin tablets is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications ( 4.2 )]
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)		Concurrent administration of ciprofloxacin tablets with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [s ee Warnings and Precautions ( 5.9 ) ] .
Drugs Known to Prolong QT Interval	Avoid Use		Ciprofloxacin tablets may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions ( 5.11 ) and Use in Specific Populations ( 8.5 )].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated		Hypoglycemia sometimes severe has been reported when ciprofloxacin tablets and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin tablets is co-administered with oral antidiabetic drugs [see Adverse Reactions (6.1)].
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)		To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin tablets discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin tablets with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)		Monitor renal function (in particular serum creatinine) when ciprofloxacin tablets is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)		The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin tablets to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin tablets with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels		Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin tablets therapy is indicated.
Ropinirole	Use with caution		Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin tablets [see Warnings and Precautions ( 5.16 ) ] .
Clozapine	Use with caution		Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin tablets are advised.
NSAIDs	Use with caution		Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution Two-fold increase in exposure		Monitor for sildenafil toxicity [see clinical Pharmacology (12.3)].
Duloxetine	Avoid Use Five-fold increase in duloxetine exposure		If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life		Ciprofloxacin tablets inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin Tablets
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)		Ciprofloxacin tablets should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration ( 2.4 ) ] .		Decrease ciprofloxacin tablets absorption, resulting in lower serum and urine levels
Probenecid		Use with caution (interferes with renal tubular secretion of ciprofloxacin tablets and increases ciprofloxacin tablets serum levels)		Potentiation of ciprofloxacin tablets toxicity may occur.

Table name:

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

Table name:

Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
StrongCYP3A4Inhibitors (e.g.,itraconazole,clarithromycin) or strongCYP2D6inhibitors (e.g.,quinidine,fluoxetine,paroxetine)	The concomitant use of aripiprazole tablets withstrong CYP3A4 orCYP2D6inhibitorsincreasedthe exposure ofaripiprazole tabletscomparedto the use of aripiprazole tabletsalone [seeCLINICALPHARMACOLOGY( 12.3)].	Withconcomitant use of aripiprazole tablets with a strongCYP3A4inhibitororCYP2D6inhibitor, reducethearipiprazole tablets dosage [see DOSAGEANDADMINISTRATION( 2.7)].
StrongCYP3A4Inducers (e.g.,carbamazepine,rifampin)	The concomitant use of aripiprazole tabletsandcarbamazepine decreased the exposure of aripiprazole tablets compared to the use of aripiprazole tablets alone [see CLINICALPHARMACOLOGY( 12.3)].	Withconcomitant use of aripiprazole tablets with a strongCYP3A4inducer, consider increasing the aripiprazole tabletsdosage [see DOSAGE ANDADMINISTRATIO( 2.7)].
AntihypertensiveDrugs	Duetoitsalphaadrenergicantagonism,aripiprazole tablets hasthepotentialtoenhance the effect of certainantihypertensive agents.	Monitor bloodpressureand adjustdoseaccordingly [seeWARNINGS AND PRECAUTIONS( 5.7)].
Benzodiazepines(e.g., lorazepam)	Theintensityofsedationwas greaterwith the combination of oral aripiprazole tabletsandlorazepam as comparedtothat observedwith aripiprazole alone.Theorthostatichypotension observed wasgreaterwith the combination as comparedtothatobserved withlorazepamalone [seeWARNINGSANDPRECAUTIONS( 5.7)]	Monitorsedation and blood pressure.Adjust dose accordingly.

Table name: Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.During concomitant use of DYLOJECT and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of DYLOJECT and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6) ]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.

Table 2: Clinically Significant Drug Interactions with Diclofenac
Drugs That Interfere with Hemostasis
Clinical Impact:
Intervention:	Monitor patients with concomitant use of DYLOJECT with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11) ].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2) ].
Intervention:	Concomitant use of DYLOJECT and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11) ]. DYLOJECT is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:
Intervention:
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of DYLOJECT with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6) ].
Digoxin
Clinical Impact:	The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of DYLOJECT and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of DYLOJECT and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of DYLOJECT and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of DYLOJECT and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention:	During concomitant use of DYLOJECT and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2) ].
Intervention:	The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of DYLOJECT and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of DYLOJECT and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Inhibitors or Inducers of Cytochrome P450 2C9
Clinical Impact:	Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Co-administration of diclofenac with CYP2C9 inhibitors (e.g. voriconazole) may enhance the exposure and toxicity of diclofenac whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of diclofenac.
Intervention:	Use caution when dosing diclofenac with CYP2C9 inhibitors or inducers, a dosage adjustment may be warranted [see Clinical Pharmacology (12.3) ].

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine concentrations approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine and carbamazepine epoxide	? carbamazepine epoxide	May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2 fold.
Valproate	? valproate	There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Factors	Dosage Adjustments for Aripiprazole
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors	Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double usual dose over 1 to 2 weeks

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide Is not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Laboratory Tests	Effect of Salicylates
Thyroid Function	Decreased PBI; increased T ₃ uptake
Urinary Sugar	False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5 g qd)
5 Hydroxyindole acetic acid	False negative with fluorometric test
Acetone, Ketone Bodies	False positive FeCl ₃ in Gerhardt reaction; red color persists with boiling
17-OH corticosteroids	False reduced values with >4.8 g qd salicylate
Vanilmandelic Acid	False reduced values
Uric Acid	May increase or decrease depending on dose
Prothrombin	Decreased levels; slightly increased prothrombin time

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Drug	Type of Interaction	Effect**
Adenosine	Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.
Alcohol	A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours.	30% increase
Allopurinol	Decreases theophylline clearance at allopurinol doses ≥600 mg/day.	25% increase
Aminoglutethimide	Increases theophylline clearance by induction of microsomal enzyme activity.	25% decrease
Carbamazepine	Similar to aminoglutethimide.	30% decrease
Cimetidine	Decreases theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase
Ciprofloxacin	Similar to cimetidine.	40% increase
Clarithromycin	Similar to erythromycin.	25% increase
Diazepam	Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.	Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram	Decreases theophylline clearance by inhibiting hydroxylation and demethylation.	50% increase
Enoxacin	Similar to cimetidine.	300% increase
Ephedrine	Synergistic CNS effects.	Increased frequency of nausea, nervousness, and insomnia.
Erythromycin	Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen	Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.	30% increase
Flurazepam	Similar to diazepam.	Similar to diazepam.
Fluvoxamine	Similar to cimetidine.	Similar to cimetidine.
Halothane	Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.	Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A	Decreases theophylline clearance.	100% increase
Isoproterenol (IV)	Increases theophylline clearance.	20% decrease
Ketamine	Pharmacologic.	May lower theophylline seizure threshold
Lithium	Theophylline increases renal lithium clearance.	Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam	Similar to diazepam.	Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.	20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine	Similar to disulfiram.	80% increase
Midazolam	Similar to diazepam.	Similar to diazepam.
Moricizine	Increases theophylline clearance.	25% decrease
Pancuronium	Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.	Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline	Decreases theophylline clearance.	30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.	25% decrease after two weeks of concurrent PB.
Phenytoin	Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.	Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone	Decreases theophylline clearance and pharmacologic interaction.	40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and pharmacologic interaction.	100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin	Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.	20-40% decrease
St. John’sWort (Hypericum Perforatum)	Decrease in theophylline plasma concentrations.	Higher doses of theophylline may be required to achieve desired effect. Stopping St. John’s Wort may result in theophylline toxicity.
Sulfinpyrazone	Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.	20% decrease
Tacrine	Similar to cimetidine, also increases renal clearance of theophylline.	90% increase
Thiabendazole	Decreases theophylline clearance.	190% increase
Ticlopidine	Decreases theophylline clearance.	60% increase
Troleandomycin	Similar to erythromycin.	33-100% increase depending on troleandomycin dose.
Verapamil	Similar to disulfiram.	20% increase

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine	Do not exceed 10 mg atorvastatin daily
Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir)	Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used.

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Summary of AED interactions with topiramate ( 7.1).
AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase ^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide ^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400mg/day	13% decrease

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitors (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
StrongCYP3A4Inhibitors (e.g.,itraconazole,clarithromycin) or strongCYP2D6inhibitors (e.g.,quinidine,fluoxetine,paroxetine)	The concomitant use of aripiprazole tablets withstrong CYP3A4 orCYP2D6inhibitorsincreasedthe exposure ofaripiprazole tabletscomparedto the use of aripiprazole tabletsalone[seeCLINICALPHARMACOLOGY(12.3)].	Withconcomitant use of aripiprazole tablets with a strongCYP3A4inhibitororCYP2D6inhibitor, reducethearipiprazole tablets dosage[see DOSAGEANDADMINISTRATION(2.7)].
StrongCYP3A4Inducers (e.g.,carbamazepine,rifampin)	The concomitant use of aripiprazole tabletsandcarbamazepine decreased the exposure of aripiprazole tablets compared to the use of aripiprazole tablets alone [see CLINICALPHARMACOLOGY(12.3)].	Withconcomitant use of aripiprazole tablets with a strongCYP3A4inducer, consider increasing the aripiprazole tabletsdosage[see DOSAGE ANDADMINISTRATIO(2.7)].
AntihypertensiveDrugs	Duetoitsalphaadrenergicantagonism,aripiprazole tablets hasthepotentialtoenhance the effect of certainantihypertensive agents.	Monitor bloodpressureand adjustdoseaccordingly[seeWARNINGS AND PRECAUTIONS(5.7)].
Benzodiazepines(e.g., lorazepam)	Theintensityofsedationwas greaterwith the combination of oral aripiprazole tabletsandlorazepam as comparedtothat observedwith aripiprazole alone.Theorthostatichypotension observed wasgreaterwith the combination as comparedtothatobserved withlorazepamalone[seeWARNINGSANDPRECAUTIONS(5.7)]	Monitorsedation and blood pressure.Adjust dose accordingly.

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol,	famotidine	nizatidine
systemic and inhaled	felodipine	norfloxacin
amoxicillin	finasteride	ofloxacin
ampicillin,	hydrocortisone	omeprazole
with or without	isoflurane	prednisone, prednisolone
sulbactam	isoniazid	ranitidine
atenolol	isradipine	rifabutin
azithromycin	influenza vaccine	roxithromycin
caffeine,	ketoconazole	sorbitol
dietary ingestion	lomefloxacin	(purgative doses do not
cefaclor	mebendazole	inhibit theophylline
co-trimoxazole	medroxyprogesterone	absorption)
(trimethoprim and	methylprednisolone	sucralfate
sulfamethoxazole)	metronidazole	terbutaline, systemic
diltiazem	metoprolol	terfenadine
dirithromycin	nadolol	tetracycline
enflurane	nifedipine	tocainide

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Calcium Channel Blockers	Antifungals	Antibiotics	Glucocorticoids	Other Drugs
diltiazem	fluconazole	azithromycin	methylprednisolone	allopurinol
nicardipine	itraconazole	clarithromycin		amiodarone
verapamil	ketoconazole	erythromycin		bromocriptine
	voriconazole	quinupristin/		colchicine
		dalfopristin		danazol
				imatinib
				metoclopramide
				nefazodone
				oral contraceptives

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C Protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 5: Established Drug Interactions Based on Studies with Didanosine or Studies with Buffered Formulations of Didanosine and Expected to Occur with Didanosine
↑Indicates increase. ↓Indicates decrease.
Drug	Effect	Clinical Comment
ganciclovir	↑didanosine concentration	If there is no suitable alternative to ganciclovir, then use in combination with didanosine with caution. Monitor for didanosine-associated toxicity.
methadone	↓didanosine concentration	If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is didanosine delayed-release capsules. Patients should be closely monitored for adequate clinical response when didanosine is coadministered with methadone, including monitoring for changes in HIV RNA viral load. Do not coadminister methadone with didanosine pediatric powder due to significant decreases in didanosine concentrations.
nelfinavir	No interaction 1 hour after didanosine	Administer nelfinavir 1 hour after didanosine.
tenofovir disoproxil fumarate	↑didanosine concentration	A dose reduction of didanosine to the following dosage once daily taken together with tenofovir disoproxil fumarate and a light meal (400 kcalories or less and 20% fat or less ) or in the fasted state is recommended.Coadministration of didanosine with food decreases didanosine concentrations. Thus, although not studied, it is possible that coadministration with heavier meals could reduce didanosine concentrations further. 250 mg (adults weighing at least 60 kg with creatinine clearance of at least 60 mL/min) 200 mg (adults weighing less than 60 kg with creatinine clearance of at least 60 mL/min) Patients should be monitored for didanosine-associated toxicities and clinical response.

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Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone Ratio Change relative to reference )		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	C_max
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 mg or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	--	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	--
	40 mg/day	4 mg/day	1.8	--
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 mg/day ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Table 5: Drug Interactions that Result in Increased Concentrations of the Concomitant Drug
Drug Class or Drug Name	Clinical Recommendations
Digoxin (P-gp substrate)	Measure serum digoxin concentrations before initiating CERDELGA. Reduce digoxin dose by 30% and continue monitoring.
Other P-gp substrates (e.g., phenytoin, colchicine, dabigatran etexilate)	Monitor therapeutic drug concentrations, as indicated, or consider reducing the dosage of the concomitant drug and titrate to clinical effect.
CYP2D6 substrates Metoprolol; tricyclic antidepressants (e.g., nortriptyline, amitriptyline, imipramine); phenothiazines (e.g., perphenazine, chloropromazine).

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CONCOMITANT DRUG	CLINICAL EFFECT(S)
Amphetamines, cocaine, other sympathomimetic agents	Additive hypertension, tachycardia, possibly cardiotoxicity
Atropine, scopolamine, antihistamines, other anticholinergic agents	Additive or super-additive tachycardia, drowsiness
Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants	Additive tachycardia, hypertension, drowsiness
Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants	Additive drowsiness and CNS depression
Disulfiram	A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge
Fluoxetine	A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine × 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days
Antipyrine, barbiturates	Decreased clearance of these agents, presumably via competitive inhibition of metabolism
Theophylline	Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine concentrations approximately 50% Decrease in levonorgestrel component by 19%
Carbamazepine and carbamazepine epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%
Carbamazepine and carbamazepine epoxide	? carbamazepine epoxide	May increase CBZ epoxide levels
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%
Valproate	↑lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold
Valproate	? valproate	There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Table 2 Steady-State Plasma Concentrations of Felbamate When Coadministered With Other AEDs
AED Coadministered	AED Concentration	Felbamate Concentration
Phenytoin	↑	↓
Valproate	↑	↔No significant effect.
Carbamazepine (CBZ) Not administered but an active metabolite of carbamazepine.CBZ epoxide	↓ ↑	↓
Phenobarbital	↑	↓

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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a = Plasma concenrtration increased 25% in some patients, generally those on a twice a day dosing regimen
of phenytoin.
b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents	Carefully monitor blood glucose ( 5.12, 7.3)

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Table 2: Clinically Significant Drug Interactions with STARLIX
Drugs That May Increase the Blood-Glucose-Lowering Effect of STARLIX and Susceptibility to Hypoglycemia
Drugs:	Nonsteroidal anti-inflammatory drugs (NSAIDs), salicylates, monoamine oxidase inhibitors, non-selective beta-adrenergic-blocking agents, anabolic hormones (e.g. methandrostenolone), guanethidine, gymnema sylvestre, glucomannan, thioctic acid, and inhibitors of CYP2C9 (e.g. amiodarone, fluconazole, voriconazole, sulfinpyrazone), alcohol.
Intervention:	Dose reductions and increased frequency of glucose monitoring may be required when STARLIX is coadministered with these drugs.
Drugs and Herbals That May Reduce the Blood-Glucose-Lowering Effect of STARLIX and Increase Susceptibility to Hyperglycemia
Drugs:	Thiazides, corticosteroids, thyroid products, sympathomimetics, somatropin, somatostatin analogues (e.g. lanreotide, octreotide), and CYP inducers (e.g. rifampin, phenytoin and St John’s Wort).
Intervention:	Dose increases and increased frequency of glucose monitoring may be required when STARLIX is coadministered with these drugs.
Drugs That May Blunt Signs and Symptoms of Hypoglycemia
Drugs:	beta-blockers, clonidine, guanethidine, and reserpine
Intervention:	Increased frequency of glucose monitoring may be required when STARLIX is coadministered with these drugs.

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Table 4. Sevelamer Drug Interactions
Oral drugs for which sevelamer did not alter the pharmacokinetics when administered concomitantly
Digoxin Enalapril Iron Metoprolol Warfarin
Oral drugs that have demonstrated interaction with sevelamer and are to be dosed separately from Renvela
	Dosing Recommendations
Ciprofloxacin Mycophenolate mofetil	Take at least 2 hours before or 6 hours after sevelamer Take at least 2 hours before sevelamer

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Table 3. Drugs That May Alter T4 and Triiodothyronine (T3) Serum Transport Without Affecting Free Thyroxine (FT4) Concentration (Euthyroidism)
Drug or Drug Class	Effect
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	These drugs may increase serum thyroxine-binding globulin (TBG) concentration.
Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid	These drugs may decrease serum TBG concentration.
Potential impact (below): Administration of these agents with SYNTHROID results in an initial transient increase in FT4. Continued administration results in a decrease in serum T4 and normal FT4 and TSH concentrations.
Salicylates (> 2 g/day)	Salicylates inhibit binding of T4 and T3 to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT4 to normal levels with sustained therapeutic serum salicylate concentrations, although total T4 levels may decrease by as much as 30%.
Other drugs: Carbamazepine Furosemide (> 80 mg IV) Heparin Hydantoins Non-Steroidal Anti-inflammatory Drugs - Fenamates	These drugs may cause protein-binding site displacement. Furosemide has been shown to inhibit the protein binding of T4 to TBG and albumin, causing an increase free T4 fraction in serum. Furosemide competes for T4-binding sites on TBG, prealbumin, and albumin, so that a single high dose can acutely lower the total T4 level. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total and free T4 may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. Closely monitor thyroid hormone parameters.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin dailyFor patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Drug	Type of Interaction	Effect**
Adenosine	Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.
Alcohol	A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours.	30% increase
Allopurinol	Decreases theophylline clearance at allopurinol doses ≥600 mg/day.	25% increase
Aminoglutethimide	Increases theophylline clearance by induction of microsomal enzyme activity.	25% decrease
Carbamazepine	Similar to aminoglutethimide.	30% decrease
Cimetidine	Decreases theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase
Ciprofloxacin	Similar to cimetidine.	40% increase
Clarithromycin	Similar to erythromycin.	25% increase
Diazepam	Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.	Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram	Decreases theophylline clearance by inhibiting hydroxylation and demethylation.	50% increase
Enoxacin	Similar to cimetidine.	300% increase
Ephedrine	Synergistic CNS effects.	Increased frequency of nausea, nervousness, and insomnia.
Erythromycin	Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen	Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.	30% increase
Flurazepam	Similar to diazepam.	Similar to diazepam.
Fluvoxamine	Similar to cimetidine.	Similar to cimetidine.
Halothane	Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.	Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A	Decreases theophylline clearance.	100% increase
Isoproterenol (IV)	Increases theophylline clearance.	20% decrease
Ketamine	Pharmacologic.	May lower theophylline seizure threshold
Lithium	Theophylline increases renal lithium clearance.	Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam	Similar to diazepam.	Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.	20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine	Similar to disulfiram.	80% increase
Midazolam	Similar to diazepam.	Similar to diazepam.
Moricizine	Increases theophylline clearance.	25% decrease
Pancuronium	Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.	Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline	Decreases theophylline clearance.	30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.	25% decrease after two weeks of concurrent PB.
Phenytoin	Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.	Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone	Decreases theophylline clearance and pharmacologic interaction.	40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and pharmacologic interaction.	100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin	Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.	20-40% decrease
St. John’sWort (Hypericum Perforatum)	Decrease in theophylline plasma concentrations.	Higher doses of theophylline may be required to achieve desired effect. Stopping St. John’s Wort may result in theophylline toxicity.
Sulfinpyrazone	Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.	20% decrease
Tacrine	Similar to cimetidine, also increases renal clearance of theophylline.	90% increase
Thiabendazole	Decreases theophylline clearance.	190% increase
Ticlopidine	Decreases theophylline clearance.	60% increase
Troleandomycin	Similar to erythromycin.	33-100% increase depending on troleandomycin dose.
Verapamil	Similar to disulfiram.	20% increase

Table 3: Clinically Relevant Interactions Affecting Drugs Co-Administered with Omeprazole and Interaction with Diagnostics
Antiretrovirals
Clinical Impact:	The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
Intervention:	Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications (4)]. Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:	Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention:	Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact:	Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].
Intervention:	A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact:	Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)]. There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention:	Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6)].
Citalopram
Clinical Impact:	Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention:	Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:	Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].
Intervention:	Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:	Potential for increased exposure of phenytoin.
Intervention:	Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:	Increased exposure of diazepam [see Clinical Pharmacology (12.3)].
Intervention:	Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:	Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention:	Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:	Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:	Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)]. See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:	Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:	See Contraindications, Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact:	Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention:	Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:	Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10), Clinical Pharmacology (12.2)].
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:	Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact:	There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:	An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:	There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:	Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin	Monitor phenytoin level (7)
Methotrexate	Monitor for methotrexate toxicity (7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased CIPRO absorption. Take 2 hours before or 6 hours after CIPRO (7)

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Table 6: Effect of Other Drugs on Voriconazole Pharmacokinetics [see CLINICAL PHARMACOLOGY (12.3)]
* Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects * Non-Nucleoside Reverse Transcriptase Inhibitors
Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (C_max and AUCτ after 200 mg q12h)	Recommendations for Voriconazole Dosage Adjustment/Comments
Rifampin* and Rifabutin* (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (400 mg q 24h)** (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (300 mg q 24h) ** (CYP450 Induction)	Slight Decrease in AUC_t	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)** (CYP450 Induction)	Significantly Reduced	Contraindicated
Low-dose Ritonavir (100 mg q12h)** (CYP450 Induction)	Reduced	Coadministration of voriconazole and low-dose ritonavir (100 mg q 12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Phenytoin* (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John’s Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives** containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole** (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIs*** (CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to voriconazole
	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Careful assessment of voriconazole effectiveness

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name:

Drugs That Interfere with Hemostasis
Clinical Impact:	Oxaprozin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of oxaprozin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of oxaprozin tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention:	Concomitant use of oxaprozin tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Oxaprozin tablets are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of oxaprozin tablets and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of oxaprozin tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of oxaprozin tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact:	The concomitant use of oxaprozin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of oxaprozin tablets and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of oxaprozin tablets and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction) because NSAID administration may result in increased plasma levels of methotrexate, especially in patients receiving high doses of methotrexate.
Intervention:	During concomitant use of oxaprozin tablets and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of oxaprozin tablets and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of oxaprozin tablets and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of oxaprozin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention:	The concomitant use of oxaprozin with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of oxaprozin tablets and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of oxaprozin tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Corticosteroids
Clinical Impact:	Concomitant use of corticosteroids with oxaprozin tablets may increase the risk of GI ulceration or bleeding.
Intervention:	Monitor patients with concomitant use of oxaprozin tablets with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)].
Glyburide
Clinical Impact:	While oxaprozin does alter the pharmacokinetics of glyburide, coadministration of oxaprozin to type II non-insulin dependent diabetic patients did not affect the area under the glucose concentration curve nor the magnitude or duration of control.
Intervention:	During concomitant use of oxaprozin tablets and glyburide, monitor patient’s blood glucose in the beginning phase of cotherapy.

Table name:

Table 5. Clinically-Significant Drug Interactions with Sertraline Hydrochloride
Monoamine Oxidase Inhibitors ( MAOIs )
Clinical Impact :	The concomitant use of SSRIs including sertraline hydrochloride and MAOIs increases the risk of serotonin syndrome.
Intervention :	Sertraline hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [ See Dosage and Administration ( 2 . 5 ), Contraindications ( 4 ), Warnings and Precautions ( 5 . 2)].
Examples :	selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
Pimozide
Clinical Impact :	Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QT prolongation and ventricular arrhythmias.
Intervention :	Concomitant use of pimozide and sertraline hydrochloride is contraindicated [ See Contraindications ( 4)].
Other Serotonergic Drugs
Clinical Impact :	The concomitant use of serotonergic drugs with sertraline hydrochloride increases the risk of serotonin syndrome.
Intervention :	Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of sertraline hydrochloride and/or concomitant serotonergic drugs [ See Warnings and Precautions ( 5 . 2)].
Examples :	other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort
Drugs that Interfere with Hemostasis ( antiplatelet agents and anticoagulants )
Clinical Impact :	The concurrent use of an antiplatelet agent or anticoagulant with sertraline hydrochloride may potentiate the risk of bleeding.
Intervention :	Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [ See Warnings and Precautions ( 5 . 3)].
Examples :	aspirin, clopidogrel, heparin, warfarin
Drugs Highly Bound to Plasma Protein
Clinical Impact :	Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of sertraline hydrochloride with another drug that is highly bound to plasma protein may increase free concentrations of sertraline hydrochloride or other tightly-bound drugs in plasma [ See Clinical Pharmacology ( 12 . 3 )].
Intervention :	Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs as warranted.
Examples :	warfarin
Drugs Metabolized by CYP2D6
Clinical Impact :	Sertraline hydrochloride is a CYP2D6 inhibitor [ See Clinical Pharmacology ( 12 . 3)]. The concomitant use of sertraline hydrochloride with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate.
Intervention :	Decrease the dosage of a CYP2D6 substrate if needed with concomitant sertraline hydrochloride use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride is discontinued.
Examples :	propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine
Phenytoin
Clinical Impact :	Phenytoin is a narrow therapeutic index drug. Sertraline hydrochloride may increase phenytoin concentrations.
Intervention :	Monitor phenytoin levels when initiating or titrating sertraline hydrochloride. Reduce phenytoin dosage if needed.
Examples :	phenytoin, fosphenytoin

Table name:

Drugs that Affect Renal Function	A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics	Dofetilide	Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
	Sotalol	Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
	Dronedarone	Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog	Teriparatide	Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement	Thyroid	Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics	Epinephrine Norepinephrine Dopamine	Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents	Succinylcholine	May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements	Calcium	If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers		Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.

Table name:

Drug	Type of Interaction	Effect**
Adenosine	Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.
Alcohol	A single large dose of alcohol (3 ml/kg of whiskey) decreases theophylline clearance for up to 24 hours.	30% increase
Allopurinol	Decreases theophylline clearance at allopurinol doses ≥600 mg/day.	25% increase
Aminoglutethimide	Increases theophylline clearance by induction of microsomal enzyme activity.	25% decrease
Carbamazepine	Similar to aminoglutethimide.	30% decrease
Cimetidine	Decreases theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase
Ciprofloxacin	Similar to cimetidine.	40% increase
Clarithromycin	Similar to erythromycin.	25% increase
Diazepam	Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.	Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram	Decreases theophylline clearance by inhibiting hydroxylation and demethylation.	50% increase
Enoxacin	Similar to cimetidine.	300% increase
Ephedrine	Synergistic CNS effects.	Increased frequency of nausea, nervousness, and insomnia.
Erythromycin	Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen	Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.	30% increase
Flurazepam	Similar to diazepam.	Similar to diazepam.
Fluvoxamine	Similar to cimetidine.	Similar to cimetidine.
Halothane	Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.	Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A	Decreases theophylline clearance.	100% increase
Isoproterenol (IV)	Increases theophylline clearance.	20% decrease
Ketamine	Pharmacologic	May lower theophylline seizure threshold.
Lithium	Theophylline increases renal lithium clearance.	Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam	Similar to diazepam.	Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.	20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine	Similar to disulfiram.	80% increase
Midazolam	Similar to diazepam.	Similar to diazepam.
Moricizine	Increases theophylline clearance.	25% decrease
Pancuronium	Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.	Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline	Decreases theophylline clearance.	30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.	25% decrease after two weeks of concurrent PB.
Phenytoin	Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.	Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone	Decreases theophylline clearance and pharmacologic interaction.	40% increase. Beta-₂ blocking effect may decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and pharmacologic interaction.	100% increase. Beta-₂ blocking effect may decrease efficacy of theophylline.
Rifampin	Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.	20 to 40% decrease
Sulfinpyrazone	Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.	20% decrease
Tacrine	Similar to cimetidine, also increases renal clearance of theophylline.	90% increase
hiabendazole	Decreases theophylline clearance.	190% increase
Ticlopidine	Decreases theophylline clearance.	60% increase
Troleandomycin	Similar to erythromycin.	33 to 100% increase depending on troleandomycin dose.
Verapamil	imilar to disulfiram.	20% increase

Table name:

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

Table name: Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.During concomitant use of diclofenac sodium delayed-release tablets and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of diclofenac sodium delayed-release tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS: Renal Toxicity and Hyperkalemia ). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.

Table 2. Clinically Significant Drug Interactions with Diclofenac
Drugs That Interfere with Hemostasis
Clinical Impact:
Intervention:	Monitor patients with concomitant use of diclofenac sodium delayed-release tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS: Hematologic Toxicity ).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ).
Intervention:	Concomitant use of diclofenac sodium delayed-release tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS: Hematologic Toxicity ). Diclofenac sodium delayed-release tablets are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:
Intervention:
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS: Renal Toxicity and Hyperkalemia ).
Digoxin
Clinical Impact:	The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of diclofenac sodium delayed-release tablets and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ).
Intervention:	The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of diclofenac sodium delayed-release tablets and pemetrexed may increase the risk of pemetrexed‑ associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or Inducers:
Clinical Impact:	Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Co-administration of diclofenac with CYP2C9 inhibitors (e.g. voriconazole) may enhance the exposure and toxicity of diclofenac whereas co‑administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of diclofenac.
Intervention:	A dosage adjustment may be warranted when diclofenac is administered with CYP2C9 inhibitors or inducers (see CLINICAL PHARMACOLOGY: Pharmacokinetics ).

Table name:

Digoxin concentrations increased greater than 50%
	Digoxin Serum Concentration Increase	Digoxin AUC Increase	Recommendations
Amiodarone	70%	NA	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30% to 50% or by modifying the dosing frequency and continue monitoring.
Captopril	58%	39%
Clarithromycin	NA	70%
Dronedarone	NA	150%
Gentamicin	129 to 212%	NA
Erthromycin	100%	NA
Itraconazole	60%	NA
Lapatinib	NA	180%
Propafenone	NA	60 to 270 %
Quinidine	100%	NA
Ranolazine	50%	NA
Ritonavir	NA	86%
Telaprevir	50%	85%
Tetracycline	100%	NA
Verapamil	50 to 75%	NA
Digoxin concentrations increased less than 50%
Atorvastatin	22%	15%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15% to 30% or by modifying the dosing frequency and continue monitoring.
Carvedilol	16%	14%
Conivaptan	33%	43%
Diltiazem	20%	NA
Indomethacin	40%	NA
Nefazodone	27%	15%
Nifedipine	45%	NA
Propantheline	24%	24%
Quinine	NA	33%
Rabeprazole	29%	19%
Saquinavir	27%	49%
Spironolactone	25%	NA
Telmisartan	20 to 49%	NA
Ticagrelor	31%	28%
Tolvaptan	30%	20%
Trimethoprim	22 to28%	NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate, and sulfasalazine			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20 % to 40 % as necessary.

Table name:

Drugs That Interfere with Hemostasis
Clinical Impact:	• Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	• During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

Table name:

AED Co-administered	AED Concentration	Topiramate Concentration
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
Phenytoin	NC or 25% increase= Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide= Is not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

Table name:

Drugs that Affect Renal Function	A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics	Dofetilide	Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
	Sotalol	Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
	Dronedarone	Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog	Teriparatide	Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement	Thyroid	Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics	Epinephrine Norepinephrine Dopamine	Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents	Succinylcholine	May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements	Calcium	If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers		Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.
Hyperpolarization-activated cyclic nucleotide-gated channel blocker	Ivabradine	Can increase the risk of bradycardia

Table name:

Table II. Clinically significant drug interactions with theophylline*.
Drug	Type of Interaction	Effect**
Adenosine	Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.
Alcohol	A single large dose of alcohol (3 ml/kg of whiskey) decreases theophylline clearance for up to 24 hours.	30% increase
Allopurinol	Decreases theophylline clearance at allopurinol doses ≥ 600 mg/day.	25% increase
Amino glutethimide	Increases theophylline clearance by induction of microsomal enzyme activity.	25% increase
Carbamazepine	Similar to aminoglutethimide	30% increase
Cimetidine	Decreases theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase
Ciprofloxacin	Similar to cimetidine.	40% increase
Clarithromycin	Similar to erythromycin.	25% increase
Diazepam	Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.	Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram	Decreases theophylline clearance by inhibiting hydroxylation and demethylation.	50% increase
Enoxacin	Similar to cimetidine.	300% increase
Ephedrine	Synergistic CNS effect	Increased frequency of nausea, nervousness, and insomnia.
Erythromycin	Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3	35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen	Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.	30% increase
Flurazepam	Similar to diazepam.	Similar to diazepam.
Fluvoxamine	Similar to cimetidine.	Similar to cimetidine
Halothane	Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.	Increase risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A	Decreases theophylline clearance.	100% increase
Isoproterenol (IV)	Increases theophylline clearance.	20% decrease
Ketamine	Pharmacologic	May lower theophylline seizure threshold.
Lithium	Theophylline increases renal lithium clearance.	Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%
Lorazepam	Similar to diazepam.	Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.	20% increase after low dose MTX, higher dose MTX may have greater effect.
Mexiletine	Similar to disulfiram.	80% increase
Midazolam	Similar to diazepam.	Similar to diazepam.
Moricizine	Increases theophylline clearance.	25% decrease
Pancuronium	Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.	Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline	Decreases theophylline clearance.	30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.	25% decrease after two weeks of concurrent PB.
Phenytoin	Phenytoin increase theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.	Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone	Decreases theophylline clearance and pharmacologic interaction.	40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and pharmacologic interaction.	100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin	Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.	20-40% decrease
Sulfinpyrazone	Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.	20% decrease
Tacrine	Similar to cimetidine, also increases renal clearance of theophylline.	90% increase
Thiabendazole	Decreases theophylline clearance.	190% increase
Ticlopidine	Decreases theophylline clearance.	60% increase
Troleandomycin	Similar to erythromycin.	33-100% increase depending on troleandomycin dose.
Verapamil	Similar to disulfiram.	20% increase

Table name:

Table 5. Clinically-Significant Drug Interactions with Sertraline Hydrochloride
Monoamine Oxidase Inhibitors ( MAOIs )
Clinical Impact :	The concomitant use of SSRIs including sertraline hydrochloride and MAOIs increases the risk of serotonin syndrome.
Intervention :	Sertraline hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [ See Dosage and Administration ( 2 . 5 ), Contraindications ( 4 ), Warnings and Precautions ( 5 . 2)].
Examples :	selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
Pimozide
Clinical Impact :	Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QT prolongation and ventricular arrhythmias.
Intervention :	Concomitant use of pimozide and sertraline hydrochloride is contraindicated [ See Contraindications ( 4)].
Other Serotonergic Drugs
Clinical Impact :	The concomitant use of serotonergic drugs with sertraline hydrochloride increases the risk of serotonin syndrome.
Intervention :	Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of sertraline hydrochloride and/or concomitant serotonergic drugs [ See Warnings and Precautions ( 5 . 2)].
Examples :	other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort
Drugs that Interfere with Hemostasis ( antiplatelet agents and anticoagulants )
Clinical Impact :	The concurrent use of an antiplatelet agent or anticoagulant with sertraline hydrochloride may potentiate the risk of bleeding.
Intervention :	Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [ See Warnings and Precautions ( 5 . 3)].
Examples :	aspirin, clopidogrel, heparin, warfarin
Drugs Highly Bound to Plasma Protein
Clinical Impact :	Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of sertraline hydrochloride with another drug that is highly bound to plasma protein may increase free concentrations of sertraline hydrochloride or other tightly-bound drugs in plasma [ See Clinical Pharmacology ( 12 . 3 )].
Intervention :	Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs as warranted.
Examples :	warfarin
Drugs Metabolized by CYP2D6
Clinical Impact :	Sertraline hydrochloride is a CYP2D6 inhibitor [ See Clinical Pharmacology ( 12 . 3)]. The concomitant use of sertraline hydrochloride with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate.
Intervention :	Decrease the dosage of a CYP2D6 substrate if needed with concomitant sertraline hydrochloride use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride is discontinued.
Examples :	propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine
Phenytoin
Clinical Impact :	Phenytoin is a narrow therapeutic index drug. Sertraline hydrochloride may increase phenytoin concentrations.
Intervention :	Monitor phenytoin levels when initiating or titrating sertraline hydrochloride. Reduce phenytoin dosage if needed.
Examples :	phenytoin, fosphenytoin

Table name: In patients receiving STRIBILD for at least 1 week, start tadalafil at 20 mg once daily. Increase tadalafil dose to 40 mg once daily based upon individual tolerability.Coadministration of STRIBILD in patients on tadalafil: Avoid use of tadalafil during the initiation of STRIBILD. Stop tadalafil at least 24 hours prior to starting STRIBILD. After at least one week following initiation of STRIBILD, resume tadalafil at 20 mg once daily. Increase tadalafil dose to 40 mg once daily based upon individual tolerability.Use of PDE-5 inhibitors for erectile dysfunction:
Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 72 hours, or tadalafil at a single dose not exceeding 10 mg in 72 hours can be used with increased monitoring for PDE-5 inhibitor associated with adverse events.

Table 6 Established and Other Potentially SignificantThis table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class: Drug Name	Effect on Concentration ↑ = Increase, ↓ = Decrease, ⇔ = No Effect	Clinical Comment
Acid Reducing Agents: AntacidsIndicates that a drug-drug interaction trial was conducted. (for example aluminum and magnesium hydroxide)	↓ elvitegravir	Elvitegravir plasma concentrations are lower when STRIBILD is administered simultaneously with antacids. It is recommended to separate STRIBILD and antacid administration by at least 2 hours.
Antiarrhythmics: e.g. amiodarone bepridil digoxin disopyramide flecainide systemic lidocaine mexiletine propafenone quinidine	↑ antiarrhythmics ↑ digoxin	Concentrations of these antiarrhythmic drugs may be increased when coadministered with STRIBILD. Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when coadministered with STRIBILD.
Antibacterials: clarithromycin telithromycin	↑ clarithromycin ↑ telithromycin ↑ cobicistat	Concentrations of clarithromycin and/or cobicistat may be altered when clarithromycin is coadministered with STRIBILD. Patients with CLcr greater than or equal to 60 mL/minute: No dose adjustment of clarithromycin is required. Patients with CLcr between 50 mL/minute and 60 mL/minute: The dose of clarithromycin should be reduced by 50%. Concentrations of telithromycin and/or cobicistat may be increased when telithromycin is coadministered with STRIBILD.
Anticoagulants: warfarin	Effect on warfarin unknown	Concentrations of warfarin may be affected upon coadministration with STRIBILD. It is recommended that the international normalized ratio (INR) be monitored upon coadministration with STRIBILD.
Anticonvulsants: carbamazepine oxcarbazepine phenobarbital phenytoin	↑ carbamazepine ↓ elvitegravir ↓ cobicistat	Coadministration of carbamazepine, oxcarbazepine, phenobarbital, or phenytoin with STRIBILD may significantly decrease cobicistat and elvitegravir plasma concentrations, which may result in loss of therapeutic effect and development of resistance. Alternative anticonvulsants should be considered.
clonazepam ethosuximide	↑ clonazepam ↑ ethosuximide	Concentrations of clonazepam and ethosuximide may be increased when coadministered with STRIBILD. Clinical monitoring is recommended upon coadministration with STRIBILD.
Antidepressants: Selective Serotonin Reuptake Inhibitors (SSRIs) e.g. paroxetine Tricyclic Antidepressants (TCAs) e.g. amitriptyline desipramine imipramine nortriptyline bupropion trazodone	↑ SSRIs ↑ TCAs ↑ trazodone	Concentrations of these antidepressant agents may be increased when coadministered with STRIBILD. Careful dose titration of the antidepressant and monitoring for antidepressant response are recommended.
Antifungals: itraconazole ketoconazole voriconazole	↑ elvitegravir ↑ cobicistat ↑ itraconazole ↑ ketoconazole ↑voriconazole	Concentrations of ketoconazole, itraconazole and voriconazole may increase upon coadministration with STRIBILD. When administering with STRIBILD, the maximum daily dose of ketoconazole or itraconazole should not exceed 200 mg per day. An assessment of benefit/risk ratio is recommended to justify use of voriconazole with STRIBILD.
Anti-gout: colchicine	↑ colchicine	STRIBILD is not recommended to be coadministered with colchicine to patients with renal or hepatic impairment. Treatment of gout-flares – coadministration of colchicine in patients receiving STRIBILD: 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days. Prophylaxis of gout-flares – coadministration of colchicine in patients receiving STRIBILD: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever – coadministration of colchicine in patients receiving STRIBILD: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial: rifabutin rifapentine	↓ elvitegravir ↓ cobicistat	Coadministration of rifabutin and rifapentine with STRIBILD may significantly decrease elvitegravir and cobicistat plasma concentrations, which may result in loss of therapeutic effect and development of resistance. Coadministration of STRIBILD with rifabutin or rifapentine is not recommended.
Beta-Blockers: e.g. metoprolol timolol	↑ beta-blockers	Concentrations of beta-blockers may be increased when coadministered with STRIBILD. Clinical monitoring is recommended and a dose decrease of the beta blocker may be necessary when these agents are coadministered with STRIBILD.
Calcium Channel Blockers: e.g. amlodipine diltiazem felodipine nicardipine nifedipine verapamil	↑ calcium channel blockers	Concentrations of calcium channel blockers may be increased when coadministered with STRIBILD. Caution is warranted and clinical monitoring is recommended upon coadministration with STRIBILD.
Corticosteroid: Systemic: dexamethasone	↓ elvitegravir ↓ cobicistat	Systemic dexamethasone, a CYP3A inducer, may significantly decrease elvitegravir and cobicistat plasma concentrations, which may result in loss of therapeutic effect and development of resistance.
Corticosteroid: Inhaled/Nasal: fluticasone	↑ fluticasone	Concomitant use of inhaled or nasal fluticasone and STRIBILD may increase plasma concentrations of fluticasone, resulting in reduced serum cortisol concentrations. Alternative corticosteroids should be considered, particularly for long term use.
Endothelin Receptor Antagonists: bosentan	↑ bosentan	Coadministration of bosentan in patients on STRIBILD: In patients who have been receiving STRIBILD for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Coadministration of STRIBILD in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of STRIBILD. After at least 10 days following the initiation of STRIBILD, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitors: atorvastatin	↑ atorvastatin	Initiate with the lowest starting dose of atorvastatin and titrate carefully while monitoring for safety.
Hormonal Contraceptives: norgestimate/ethinyl estradiol	↑ norgestimate ↓ ethinyl estradiol	The effects of increases in the concentration of the progestational component norgestimate are not fully known and can include increased risk of insulin resistance, dyslipidemia, acne, and venous thrombosis. The potential risks and benefits associated with coadministration of norgestimate/ethinyl estradiol with STRIBILD should be considered, particularly in women who have risk factors for these events. Coadministration of STRIBILD with other hormonal contraceptives (e.g., contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestogens other than norgestimate has not been studied; therefore, alternative (non-hormonal) methods of contraception can be considered.
Immuno-suppressants: e.g. cyclosporine sirolimus tacrolimus	↑ immuno-suppressants	Concentrations of these immunosuppressant agents may be increased when coadministered with STRIBILD. Therapeutic monitoring of the immunosuppressive agents is recommended upon coadministration with STRIBILD.
Narcotic Analgesics: buprenorphine/ naloxone	↑ buprenorphine ↑ norbuprenorphine ↓ naloxone	Concentrations of buprenorphine and norbuprenorphine are increased when coadministered with STRIBILD. No dose adjustment of buprenorphine/naloxone is required upon coadministration with STRIBILD. Patients should be closely monitored for sedation and cognitive effects.
Inhaled Beta Agonist: salmeterol	↑ salmeterol	Coadministration of salmeterol and STRIBILD is not recommended. Coadministration of salmeterol with STRIBILD may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Neuroleptics: e.g. perphenazine risperidone thioridazine	↑ neuroleptics	A decrease in dose of the neuroleptic may be needed when coadministered with STRIBILD.
Phosphodiesterase-5 (PDE5) Inhibitors: sildenafil tadalafil vardenafil	↑ PDE5 inhibitors	Coadministration with STRIBILD may result in an increase in PDE-5 inhibitor associated adverse reactions, including hypotension, syncope, visual disturbances, and priapism. Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Use of sildenafil is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH). The following dose adjustments are recommended for the use of tadalafil with STRIBILD: Coadministration of tadalafil in patients on STRIBILD:
Sedative/hypnotics: Benzodiazepines: e.g. Parenterally administered midazolam clorazepate diazepam estazolam flurazepam buspirone zolpidem	↑ sedatives/hypnotics	Concomitant use of parenteral midazolam with STRIBILD may increase plasma concentrations of midazolam. Coadministration should be done in a setting that ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Coadministration of oral midazolam with STRIBILD is contraindicated. With other sedative/hypnotics, dose reduction may be necessary and clinical monitoring is recommended.

Table name:

AED Co - administered	AED Concentration	Topiramate Concentration
^a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
^b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
Phenytoin	NC or 25% increase ^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide ^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

Table name:

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( , , , , , , , ) 2.3 2.4 4 5.1 7.1 7.2 7.3 12.3
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

Table name:

Antibiotics	Anticonvulsants	Other Drugs / Dietary Supplements
nafcillin	carbamazepine	bosentan	St. John’s Wort
rifampin	oxcarbazepine	octreotide
	phenobarbital	orlistat
	phenytoin	sulfinpyrazone
		terbinafine
		ticlopidine

Table name:

Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

Table name:

Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion –the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration		Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen		Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4 , 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.12 , 7.3)

Table name:

Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name:

AED Co - administered	AED Concentration	Topiramate Concentration
Phenytoin	NCor25%increase^a	48%decrease
Carbamazepine(CBZ)	NC	40%decrease
CBZepoxide^b	NC	NE
Valproic acid	11%decrease	14%decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NCatTPM dosesupto400 mg/day	13%decrease

Table name:

Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.9)].
Benzodiazepines (e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.9)]	Monitor sedation and blood pressure. Adjust dose accordingly.

Table name:

Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.7)].
Benzodiazepines (e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.7)]	Monitor sedation and blood pressure. Adjust dose accordingly.

Table name:

Laboratory Tests	Effect of Salicylates
Thyroid Function	Decreased PBI; increased T₃ uptake
Urinary Sugar	False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5 g qd)
5 Hydroxyindole Acetic Acid	False negative with fluorometric test
Acetone, Ketone Bodies	False positive FeCl₃ in Gerhardt reaction; red color persists with boiling
17-OH corticosteroids	False reduced values with >4.8 g qd salicylate
Vanilmandelic Acid	False reduced values
Uric Acid	May increase or decrease depending on dose
Prothrombin	Decreased levels; slightly increased prothrombin time

Table name:

Bleeding times
Clinical Impact:	Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention:	This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact:	The administration of naproxen may result in increased urinary values for 17 ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention:	Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact:	Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention:	This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.

Table name:

Antibiotics
ciprofloxacin
gentamicin
tobramycin
trimethoprim with sulfamethoxazole
vancomycin

Antineoplastic
melphalan

Antifungals
amphotericin B
ketoconazole

Anti-Inflammatory Drugs
azapropazon
colchicine
diclofenac
naproxen
sulindac

Gastrointestinal Agents
cimetidine
ranitidine

Immunosuppressives
tacrolimus

Other Drugs
fibric acid derivatives
(e.g., bezafibrate, fenofibrate)

Table name:

Table 9. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug Name	Effect on Concentration of Lopinavir or Concomitant Drug	Clinical Comments
HIV-1 Antiviral Agents
Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz, nevirapine	↓ lopinavir	KALETRA dose increase is recommended in all patients [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)]. Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz. Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz. KALETRA should not be administered once daily in combination with efavirenz or nevirapine [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine	↑ lopinavir	Appropriate doses of the combination with respect to safety and efficacy have not been established.
Nucleoside Reverse Transcriptase Inhibitor: didanosine		KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).
Nucleoside Reverse Transcriptase Inhibitor: tenofovir	↑ tenofovir	KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitor: abacavir zidovudine	↓ abacavir ↓ zidovudine	KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.
HIV-1 Protease Inhibitor: amprenavir*	↑ amprenavir ↓ lopinavir	KALETRA should not be administered once daily in combination with amprenavir [see Dosage and Administration (2.1)].
HIV-1 Protease Inhibitor: fosamprenavir/ritonavir	↓ amprenavir ↓ lopinavir	An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: indinavir*	↑ indinavir	Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily [see Clinical Pharmacology (12.3)]. KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor: nelfinavir*	↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir	KALETRA should not be administered once daily in combination with nelfinavir [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
HIV-1 Protease Inhibitor: ritonavir*	↑ lopinavir	Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: saquinavir*	↑ saquinavir	The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor: tipranavir	↓ lopinavir AUC and C_min	KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily).
HIV CCR5 – Antagonist: maraviroc	↑ maraviroc	Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry^® (maraviroc).
Other Agents
Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), quinidine	↑ antiarrhythmics	Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.
Anticancer Agents: vincristine, vinblastine, dasatinib, nilotinib	↑ anticancer agents	Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents. For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.
Anticoagulant: warfarin		Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: carbamazepine, phenobarbital, phenytoin	↓ lopinavir ↓ phenytoin	KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
Antidepressant: bupropion	↓ bupropion ↓ active metabolite, hydroxybupropion	Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant: trazodone	↑ trazodone	Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-infective: clarithromycin	↑ clarithromycin	For patients with renal impairment, the following dosage adjustments should be considered: • For patients with CL_CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. • For patients with CL_CR < 30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary.
Antifungals: ketoconazole*, itraconazole, voriconazole	↑ ketoconazole ↑ itraconazole ↓ voriconazole	High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended. Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients.
Anti-gout: colchicine	↑ colchicine	Patients with renal or hepatic impairment should not be given colchicine with KALETRA. Treatment of gout flares-co-administration of colchicine in patients on KALETRA: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on KALETRA: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial: rifabutin*	↑ rifabutin and rifabutin metabolite	Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antimycobacterial: rifampin	↓ lopinavir	May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone [see Clinical Pharmacology (12.3) for magnitude of interaction].
Antiparasitic: atovaquone	↓ atovaquone	Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Benzodiazepines: parenterally administered midazolam	↑ midazolam	Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam [see Contraindications (4)]. If KALETRA is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Calcium Channel Blockers: dihydropyridine, felodipine, nifedipine, nicardipine	↑ dihydropyridine calcium channel blockers	Caution is warranted and clinical monitoring of patients is recommended.
Contraceptive: ethinyl estradiol*	↓ ethinyl estradiol	Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.
Corticosteroid: dexamethasone	↓ lopinavir	Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly.
disulfiram/metronidazole		KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Endothelin Receptor Antagonists: bosentan	↑ bosentan	Co-administration of bosentan in patients on KALETRA: In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Co-administration of KALETRA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA. After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin	↑ atorvastatin ↑ rosuvastatin	Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day. See Drugs with No Observed or Predicted Interactions with KALETRA (7.4) and Clinical Pharmacology (12.3) for drug interaction data with other HMG-CoA reductase inhibitors.
Immunosuppressants: cyclosporine, tacrolimus, rapamycin	↑ immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Inhaled Steroid: fluticasone	↑ fluticasone	Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect.
Long-acting beta-adrenoceptor Agonist: salmeterol	↑ salmeterol	Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic: methadone* fentanyl	↓ methadone ↑ fentanyl	Dosage of methadone may need to be increased when co-administered with KALETRA. Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA.
PDE5 inhibitors: sildenafil, tadalafil, vardenafil	↑ sildenafil ↑ tadalafil ↑ vardenafil	Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio^®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA [see Contraindications (4)]. The following dose adjustments are recommended for use of tadalafil (Adcirca^®) with KALETRA: Co-administration of ADCIRCA in patients on KALETRA: In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Co-administration of KALETRA in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: It is recommended not to exceed the following doses: • Sildenafil: 25 mg every 48 hours • Tadalafil: 10 mg every 72 hours • Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events.
* see Clinical Pharmacology (12.3) for magnitude of interaction.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion–the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide(including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T ₄ and T ₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide(including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT ₄. Continued administration results in a decrease in serum T ₄, and normal FT ₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T ₄ and T ₃ to TBG and transthyretin. An initial increase in serum FT ₄ is followed by return of FT ₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T ₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T ₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5’-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T ₄ to T ₃, leading to decreased T ₃ levels. However, serum T ₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T ₃ and T ₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T ₃ concentrations by 30% with minimal change in serum T ₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T ₃ and T ₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.

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Table 7 Summary of AED Interactions with Oxcarbazepine Tablets, USP
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Tablets Dose (mg/day)	Influence of Oxcarbazepine Tablets on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400-2000	900	nc nc denotes a mean change of less than 10%	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100-150	600-1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250-500	600-1800 >1200-2400	nc ^, Pediatrics up to 40% increase Mean increase in adults at high oxcarbazepine tablets, USP doses [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400-2800	600-1800	nc	18% decrease [CI: 13% decrease, 40% decrease]

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Table 3: Clinically Significant Drug Interactions with Celecoxib
Drugs That Interfere w ith Hemostasis
Clinical Impact:	Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of Celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of celecoxib with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11) ].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2) ]. In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200 to 400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100 to 325 mg).
Intervention:	Concomitant use of celecoxib and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11) ]. Celecoxib is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of celecoxib and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of celecoxib and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6) ]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of celecoxib with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6) ].
Digoxin
Clinical Impact:	The concomitant use of Celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of celecoxib and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of celecoxib and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Celecoxib has no effect on methotrexate pharmacokinetics.
Intervention:	During concomitant use of celecoxib and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of celecoxib and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of celecoxib and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs a nd Salicylates
Clinical Impact:	Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2) ].
Intervention:	The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of celecoxib and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of celecoxib and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or inducers
Clinical Impact:	Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib.
Intervention	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [see Clinical Pharmacology (12.3) ].
CYP2D6 substrates
Clinical Impact:	In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs.
Intervention	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [see Clinical Pharmacology (12.3) ].
Corticosteroids
Clinical Impact:	Concomitant use of corticosteroids with celecoxib may increase the risk of GI ulceration or bleeding.
Intervention	Monitor patients with concomitant use of celecoxib with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2) ].

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Interacting Drug	Interaction
Multivalent cation-containing products including: antacids, sucralfate, multivitamins	Decreased moxifloxacin hydrochloride absorption. Take moxifloxacin hydrochloride tablet at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time/INR, and bleeding. (6, 7.2, 12.3)
Class IA and Class III antiarrhythmics:	Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.6, 7.5)
Antidiabetic agents	Carefully monitor blood glucose. (5.11, 7.3)

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Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of aripiprazole with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)] .	With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)] .
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)] .	With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)] .
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.7)] .
Benzodiazepines(e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.7)] .	Monitor sedation and blood pressure. Adjust dose accordingly.

Table 6 Established and Other Potentially SignificantThis table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class: Drug Name	Effect on Concentration ↑ = Increase, ↓ = Decrease, ⇔ = No Effect	Clinical Comment
Acid Reducing Agents: AntacidsIndicates that a drug-drug interaction trial was conducted. (for example aluminum and magnesium hydroxide)	↓ elvitegravir	Elvitegravir plasma concentrations are lower when STRIBILD is administered simultaneously with antacids. It is recommended to separate STRIBILD and antacid administration by at least 2 hours.
Antiarrhythmics: e.g. amiodarone bepridil digoxin disopyramide flecainide systemic lidocaine mexiletine propafenone quinidine	↑ antiarrhythmics ↑ digoxin	Concentrations of these antiarrhythmic drugs may be increased when coadministered with STRIBILD. Caution is warranted and therapeutic concentration monitoring, if available, is recommended for antiarrhythmics when coadministered with STRIBILD.
Antibacterials: clarithromycin telithromycin	↑ clarithromycin ↑ telithromycin ↑ cobicistat	Concentrations of clarithromycin and/or cobicistat may be altered when clarithromycin is coadministered with STRIBILD. Patients with CLcr greater than or equal to 60 mL/min: No dose adjustment of clarithromycin is required. Patients with CLcr between 50 mL/min and 60 mL/min: The dose of clarithromycin should be reduced by 50%. Concentrations of telithromycin and/or cobicistat may be increased when telithromycin is coadministered with STRIBILD.
Anticoagulants: warfarin	Effect on warfarin unknown	Concentrations of warfarin may be affected upon coadministration with STRIBILD. It is recommended that the international normalized ratio (INR) be monitored upon coadministration with STRIBILD.
Anticonvulsants: carbamazepine oxcarbazepine phenobarbital phenytoin	↑ carbamazepine ↓ elvitegravir ↓ cobicistat	Coadministration of carbamazepine, oxcarbazepine, phenobarbital, or phenytoin with STRIBILD may significantly decrease cobicistat and elvitegravir plasma concentrations, which may result in loss of therapeutic effect and development of resistance. Alternative anticonvulsants should be considered.
clonazepam ethosuximide	↑ clonazepam ↑ ethosuximide	Concentrations of clonazepam and ethosuximide may be increased when coadministered with STRIBILD. Clinical monitoring is recommended upon coadministration with STRIBILD.
Antidepressants: Selective Serotonin Reuptake Inhibitors (SSRIs) e.g. paroxetine Tricyclic Antidepressants (TCAs) e.g. amitriptyline desipramine imipramine nortriptyline buproprion trazodone	↑ SSRIs ↑ TCAs ↑ trazodone	Concentrations of these antidepressant agents may be increased when coadministered with STRIBILD. Careful dose titration of the antidepressant and monitoring for antidepressant response are recommended.
Antifungals: itraconazole ketoconazole voriconazole	↑ elvitegravir ↑ cobicistat ↑ itraconazole ↑ ketoconazole ↑voriconazole	Concentrations of ketoconazole, itraconazole and voriconazole may increase upon coadministration with STRIBILD. When administering with STRIBILD, the maximum daily dose of ketoconazole or itraconazole should not exceed 200 mg per day. An assessment of benefit/risk ratio is recommended to justify use of voriconazole with STRIBILD.
Anti-gout: colchicine	↑ colchicine	STRIBILD is not recommended to be coadministered with colchicine to patients with renal or hepatic impairment. Treatment of gout-flares – coadministration of colchicine in patients receiving STRIBILD: 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course to be repeated no earlier than 3 days. Prophylaxis of gout-flares – coadministration of colchicine in patients receiving STRIBILD: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever – coadministration of colchicine in patients receiving STRIBILD: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial: rifabutin rifapentine	↓ elvitegravir ↓ cobicistat	Coadministration of rifabutin and rifapentine with STRIBILD may significantly decrease elvitegravir and cobicistat plasma concentrations, which may result in loss of therapeutic effect and development of resistance. Coadministration of STRIBILD with rifabutin or rifapentine is not recommended.
Beta-Blockers: e.g. metoprolol timolol	↑ beta-blockers	Concentrations of beta-blockers may be increased when coadministered with STRIBILD. Clinical monitoring is recommended and a dose decrease of the beta blocker may be necessary when these agents are coadministered with STRIBILD.
Calcium Channel Blockers: e.g. amlodipine diltiazem felodipine nicardipine nifedipine verapamil	↑ calcium channel blockers	Concentrations of calcium channel blockers may be increased when coadministered with STRIBILD. Caution is warranted and clinical monitoring is recommended upon coadministration with STRIBILD.
Corticosteroid: Systemic: dexamethasone	↓ elvitegravir ↓ cobicistat	Systemic dexamethasone, a CYP3A inducer, may significantly decrease elvitegravir and cobicistat plasma concentrations, which may result in loss of therapeutic effect and development of resistance.
Corticosteroid: Inhaled/Nasal: fluticasone	↑ fluticasone	Concomitant use of inhaled or nasal fluticasone and STRIBILD may increase plasma concentrations of fluticasone, resulting in reduced serum cortisol concentrations. Alternative corticosteroids should be considered, particularly for long term use.
Endothelin Receptor Antagonists: bosentan	↑ bosentan	Coadministration of bosentan in patients on STRIBILD: In patients who have been receiving STRIBILD for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Coadministration of STRIBILD in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of STRIBILD. After at least 10 days following the initiation of STRIBILD, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitors: atorvastatin	↑ atorvastatin	Initiate with the lowest starting dose of atorvastatin and titrate carefully while monitoring for safety.
Hormonal Contraceptives: norgestimate/ethinyl estradiol	↑ norgestimate ↓ ethinyl estradiol	The effects of increases in the concentration of the progestational component norgestimate are not fully known and can include increased risk of insulin resistance, dyslipidemia, acne, and venous thrombosis. The potential risks and benefits associated with coadministration of norgestimate/ethinyl estradiol with STRIBILD should be considered, particularly in women who have risk factors for these events. Coadministration of STRIBILD with other hormonal contraceptives (e.g., contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestogens other than norgestimate has not been studied; therefore, alternative (non-hormonal) methods of contraception can be considered.
Immuno-suppressants: e.g. cyclosporine sirolimus tacrolimus	↑ immuno-suppressants	Concentrations of these immunosuppressant agents may be increased when coadministered with STRIBILD. Therapeutic monitoring of the immunosuppressive agents is recommended upon coadministration with STRIBILD.
Narcotic Analgesics: buprenorphine/ naloxone	↑ buprenorphine ↑ norbuprenorphine ↓ naloxone	Concentrations of buprenorphine and norbuprenorphine are increased when coadministered with STRIBILD. No dose adjustment of buprenorphine/naloxone is required upon coadministration with STRIBILD. Patients should be closely monitored for sedation and cognitive effects.
Inhaled Beta Agonist: salmeterol	↑ salmeterol	Coadministration of salmeterol and STRIBILD is not recommended. Coadministration of salmeterol with STRIBILD may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Neuroleptics: e.g. perphenazine risperidone thioridazine	↑ neuroleptics	A decrease in dose of the neuroleptic may be needed when coadministered with STRIBILD.
Phosphodiesterase-5 (PDE5) Inhibitors: sildenafil tadalafil vardenafil	↑ PDE5 inhibitors	Coadministration with STRIBILD may result in an increase in PDE-5 inhibitor associated adverse reactions, including hypotension, syncope, visual disturbances, and priapism. Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Use of sildenafil is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH). The following dose adjustments are recommended for the use of tadalafil with STRIBILD: Coadministration of tadalafil in patients on STRIBILD:
Sedative/hypnotics: Benzodiazepines: e.g. Parenterally administered midazolam clorazepate diazepam estazolam flurazepam buspirone zolpidem	↑ sedatives/hypnotics	Concomitant use of parenteral midazolam with STRIBILD may increase plasma concentrations of midazolam. Coadministration should be done in a setting that ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Coadministration of oral midazolam with STRIBILD is contraindicated. With other sedative/hypnotics, dose reduction may be necessary and clinical monitoring is recommended.

Table name:

Table 7. Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class: Drug Name	Effect on Concentration of Delavirdine or Concomitant Drug	Clinical Comment
HIV-Antiviral Agents
Amprenavir	↑Amprenavir	Appropriate doses of this combination with respect to safety, efficacy, and pharmacokinetics have not been established.
Didanosine^a	↓Delavirdine↓Didanosine	Administration of didanosine (buffered tablets) and RESCRIPTOR should be separated by at least 1 hour.
Indinavir^a	↑Indinavir	A dose reduction of indinavir to 600 mg 3 times daily should be considered when RESCRIPTOR and indinavir are coadministered.
Lopinavir/Ritonavir	↑Lopinavir↑Ritonavir	Appropriate doses of this combination with respect to safety, efficacy, and pharmacokinetics have not been established.
Nelfinavir^a	↑Nelfinavir↓Delavirdine	Appropriate doses of this combination with respect to safety, efficacy, and pharmacokinetics have not been established. (See CLINICAL PHARMACOLOGY: Tables 1 and 2.)
Ritonavir	↑Ritonavir	Appropriate doses of this combination with respect to safety, efficacy, and pharmacokinetics have not been established.
Saquinavir^a	↑Saquinavir	A dose reduction of saquinavir (soft gelatin capsules) may be considered when RESCRIPTOR and saquinavir are coadministered (see CLINICAL PHARMACOLOGY: Table 1). Appropriate doses with respect to safety, efficacy, and pharmacokinetics have not been established.
Other Agents
Acid blockers: Antacids^a	↓Delavirdine	Doses of an antacid and RESCRIPTOR should be separated by at least 1 hour, because the absorption of delavirdine is reduced when coadministered with antacids.
Acid blockers: Antacids^a	↓Delavirdine
Histamine H₂-receptor antagonists: Cimetidine, famotidine, nizatidine, ranitidine	↓Delavirdine	These agents increase gastric pH and may reduce the absorption of delavirdine. Although the effect of these drugs on delavirdine absorption has not been evaluated, chronic use of these drugs with RESCRIPTOR is not recommended.
Proton pump inhibitors: Omeprazole, lansoprazole	↓Delavirdine	These agents increase gastric pH and may reduce the absorption of delavirdine. Although the effect of these drugs on delavirdine absorption has not been evaluated, chronic use of these drugs with RESCRIPTOR is not recommended.
Amphetamines	↑Amphetamines	Use with caution.
Antidepressant: Trazodone	↑Trazodone	Concomitant use of trazodone and RESCRIPTOR may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as RESCRIPTOR, the combination should be used with caution and a lower dose of trazadone should be considered.
Antiarrhythmics: Bepridil	↑Antiarrhythmics	Use with caution. Increased bepridil exposure may be associated with life-threatening reactions such as cardiac arrhythmias.
Amiodarone,lidocaine (systemic), quinidine, flecainide, propafenone		Caution is warranted and therapeutic concentration monitoring is recommended, if available, for antiarrhythmics when coadministered with RESCRIPTOR.
Anticoagulant: Warfarin	↑Warfarin	It is recommended that INR (international normalized ratio) be monitored.
Anti-infective: Clarithromycin^a	↑Clarithromycin	When coadministered with RESCRIPTOR, clarithromycin should be adjusted in patients with impaired renal function: For patients with CL_CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CL_CR <30 mL/min the dose of clarithromycin should be reduced by 75%.
Calcium channel blockers: Amlodipine, diltiazem, felodipine, isradipine, nifedipine, nicardipine, nimodipine, nisoldipine, verapamil	↑Calcium channel blockers	Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid: Dexamethasone	↓Delavirdine	Use with caution. RESCRIPTOR may be less effective due to decreased delavirdine plasma concentrations in patients taking these agents concomitantly.
Erectile dysfunction agents: Sildenafil	↑Sildenafil	Sildenafil should not exceed a maximum single dose of 25 mg in a 48-hour period.
HMG-CoA reductase inhibitors: Atorvastatin, cerivastatin, fluvastatin	↑Atorvastatin ↑Cerivastatin↑Fluvastatin	Use lowest possible dose of atorvastatin or cerivastatin, or fluvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin in combination with RESCRIPTOR.
Immunosuppressants: Cyclosporine, tacrolimus, rapamycin	↑Immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with RESCRIPTOR.
Inhaled/nasal steroid: Fluticasone	↑Fluticasone	Concomitant use of fluticasone propionate and RESCRIPTOR may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use.
Narcotic analgesic: Methadone	↑Methadone	Dosage of methadone may need to be decreased when coadministered with RESCRIPTOR.
Oral contraceptives: Ethinyl estradiol	↑Ethinyl estradiol	Concentrations of ethinyl estradiol may increase. However, the clinical significance is unknown.

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents	Carefully monitor blood glucose ( 5.12, 7.3)

Table name:

Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin	Monitor phenytoin level (7)
Methotrexate	Monitor for methotrexate toxicity (7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine (7)

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

Table name:

Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. ₄ ₃
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT , is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. ₄ ₄ ₄ ₄ ₃ ₄ ₄ ₄
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. ₄
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T to T , leading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T and T levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). ₄ ₃ ₃ ₄ ₃ ₄ ₃ ₄ ₃ ₄
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of I, I, and Tc. ¹²³ ¹³¹ ^99m
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.10, 7.3)

Table name:

Table 7: Summary of AED Interactions with TRILEPTAL
AED Coadministered	Dose of AED (mg/day)	TRILEPTAL Dose (mg/day)	Influence of TRILEPTAL on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400-2000	900	nc¹	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100-150	600-1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250-500	600-1800 >1200-2400	nc^1,2 up to 40% increase³ [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400-2800	600-1800	nc¹	18% decrease [CI: 13% decrease, 40% decrease]
Lamotrigine	200	1200	nc¹	nc¹

Table name:

Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

Table name:

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

Table name:

AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxideIs not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

Table name:

AED Coadministered	AED Concentration	Topiramate Concentration
a= Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. b= Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. NE = Not Evaluated
Phenytoin	NC or 25% increasea	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxideb	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

Table name:

Table 3Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

Table name:

Table 3: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [See Clinical Pharmacology (12.3)]
Concomitant Drug Class: Drug Name	Effect on Concentration of Etravirine or Concomitant Drug	Clinical Comment
↑ = increase, ↓ = decrease, ↔ = no change
HIV-Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
efavirenzThe interaction between INTELENCE^® and the drug was evaluated in a clinical study. All other drug interactions shown are predicted. nevirapine	↓ etravirine	Combining two NNRTIs has not been shown to be beneficial. Concomitant use of INTELENCE^® with efavirenz or nevirapine may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE^®. INTELENCE^® and other NNRTIs should not be co-administered.
delavirdine	↑ etravirine	Combining two NNRTIs has not been shown to be beneficial. INTELENCE^® and delavirdine should not be co-administered.
rilpivirine	↓ rilpivirine ↔ etravirine	Combining two NNRTIs has not been shown to be beneficial. INTELENCE^® and rilpivirine should not be coadministered.
HIV-Antiviral Agents: Protease Inhibitors (PIs)
atazanavir (without ritonavir)	↓ atazanavir	Concomitant use of INTELENCE^® with atazanavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of atazanavir. INTELENCE^® should not be co-administered with atazanavir without low-dose ritonavir.
atazanavir/ritonavir	↓ atazanavir ↑ etravirine	Concomitant use of INTELENCE^® with atazanavir/ritonavir may cause a significant decrease in atazanavir C_min and loss of therapeutic effect of atazanavir. In addition, the mean systemic exposure (AUC) of etravirine after co-administration of INTELENCE^® with atazanavir/ritonavir is anticipated to be higher than the mean systemic exposure of etravirine observed in the Phase 3 trials after co-administration of INTELENCE^® and darunavir/ritonavir (as part of the background regimen). INTELENCE^® and atazanavir/ritonavir should not be co-administered.
darunavir/ritonavir	↓ etravirine	The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE^® was co-administered with darunavir/ritonavir. Because all subjects in the Phase 3 trials received darunavir/ritonavir as part of the background regimen and etravirine exposures from these trials were determined to be safe and effective, INTELENCE^® and darunavir/ritonavir can be co-administered without dose adjustments.
fosamprenavir (without ritonavir)	↑ amprenavir	Concomitant use of INTELENCE^® with fosamprenavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of amprenavir. INTELENCE^® should not be co-administered with fosamprenavir without low-dose ritonavir.
fosamprenavir/ritonavir	↑ amprenavir	Due to a significant increase in the systemic exposure of amprenavir, the appropriate doses of the combination of INTELENCE^® and fosamprenavir/ritonavir have not been established. INTELENCE^® and fosamprenavir/ritonavir should not be co-administered.
indinavir (without ritonavir)	↓ indinavir	Concomitant use of INTELENCE^® with indinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of indinavir. INTELENCE^® should not be co-administered with indinavir without low-dose ritonavir.
lopinavir/ritonavir	↓ etravirine	The mean systemic exposure (AUC) of etravirine was reduced after co-administration of INTELENCE^® with lopinavir/ritonavir (tablet). Because the reduction in the mean systemic exposures of etravirine in the presence of lopinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE^® and lopinavir/ritonavir can be co-administered without dose adjustments.
nelfinavir (without ritonavir)	↑ nelfinavir	Concomitant use of INTELENCE^® with nelfinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of nelfinavir. INTELENCE^® should not be co-administered with nelfinavir without low-dose ritonavir.
ritonavir	↓ etravirine	Concomitant use of INTELENCE^® with ritonavir 600 mg twice daily may cause a significant decrease in the plasma concentration of etravirine and loss of therapeutic effect of INTELENCE^®. INTELENCE^® and ritonavir 600 mg twice daily should not be co-administered.
saquinavir/ritonavir	↓ etravirine	The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE^® was co-administered with saquinavir/ritonavir. Because the reduction in the mean systemic exposures of etravirine in the presence of saquinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE^® and saquinavir/ritonavir can be co-administered without dose adjustments.
tipranavir/ritonavir	↓ etravirine	Concomitant use of INTELENCE^® with tipranavir/ritonavir may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE^®. INTELENCE^® and tipranavir/ritonavir should not be co-administered.
CCR5 Antagonists
maraviroc	↔ etravirine ↓ maraviroc	When INTELENCE^® is co-administered with maraviroc in the absence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 600 mg twice daily. No dose adjustment of INTELENCE^® is needed.
maraviroc/darunavir/ritonavir	↔ etravirine ↑ maraviroc	When INTELENCE^® is co-administered with maraviroc in the presence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 150 mg twice daily. No dose adjustment of INTELENCE^® is needed.
Other Agents
Antiarrhythmics: digoxin	↔ etravirine ↑ digoxin	For patients who are initiating a combination of INTELENCE^® and digoxin, the lowest dose of digoxin should initially be prescribed. For patients on a stable digoxin regimen and initiating INTELENCE^®, no dose adjustment of either INTELENCE^® or digoxin is needed. The serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.
amiodarone, bepridil, disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine	↓ antiarrhythmics	Concentrations of these antiarrhythmics may be decreased when co-administered with INTELENCE^®. INTELENCE^® and antiarrhythmics should be co-administered with caution. Drug concentration monitoring is recommended, if available.
Anticoagulants: warfarin	↑ anticoagulants	Warfarin concentrations may be increased when co-administered with INTELENCE^®. The international normalized ratio (INR) should be monitored when warfarin is combined with INTELENCE^®.
Anticonvulsants: carbamazepine, phenobarbital, phenytoin	↓ etravirine	Carbamazepine, phenobarbital and phenytoin are inducers of CYP450 enzymes. INTELENCE^® should not be used in combination with carbamazepine, phenobarbital, or phenytoin as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE^®.
Antifungals: fluconazole, voriconazole	↑ etravirine ↔ fluconazole ↑ voriconazole	Co-administration of etravirine and fluconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and fluconazole should be co-administered with caution. No dose adjustment of INTELENCE^® or fluconazole is needed.
		Co-administration of etravirine and voriconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and voriconazole should be co-administered with caution. No dose adjustment of INTELENCE^® or voriconazole is needed.
Antifungals: itraconazole, ketoconazole, posaconazole	↑ etravirine ↓ itraconazole ↓ ketoconazole ↔ posaconazole	Posaconazole, a potent inhibitor of CYP3A4, may increase plasma concentrations of etravirine. Itraconazole and ketoconazole are potent inhibitors as well as substrates of CYP3A4. Concomitant systemic use of itraconazole or ketoconazole and INTELENCE^® may increase plasma concentrations of etravirine. Simultaneously, plasma concentrations of itraconazole or ketoconazole may be decreased by INTELENCE^®. Dose adjustments for itraconazole, ketoconazole or posaconazole may be necessary depending on the other co-administered drugs.
Antiinfectives: clarithromycin	↑ etravirine ↓ clarithromycin ↑ 14-OH-clarithromycin	Clarithromycin exposure was decreased by INTELENCE^®; however, concentrations of the active metabolite, 14-hydroxy-clarithromycin, were increased. Because 14-hydroxy-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered for the treatment of MAC.
Antimycobacterials: rifampin, rifapentine	↓ etravirine	Rifampin and rifapentine are potent inducers of CYP450 enzymes. INTELENCE^® should not be used with rifampin or rifapentine as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE^®.
Antimycobacterials: rifabutin	↓ etravirine ↓ rifabutin ↓ 25-O-desacetylrifabutin	If INTELENCE^® is NOT co-administered with a protease inhibitor/ritonavir, then rifabutin at a dose of 300 mg once daily is recommended. If INTELENCE^® is co-administered with darunavir/ritonavir, lopinavir/ritonavir or saquinavir/ritonavir, then rifabutin should not be co-administered due to the potential for significant reductions in etravirine exposure.
Benzodiazepines: diazepam	↑ diazepam	Concomitant use of INTELENCE^® with diazepam may increase plasma concentrations of diazepam. A decrease in diazepam dose may be needed.
Corticosteroids: dexamethasone (systemic)	↓ etravirine	Systemic dexamethasone induces CYP3A and can decrease etravirine plasma concentrations. This may result in loss of therapeutic effect of INTELENCE^®. Systemic dexamethasone should be used with caution or alternatives should be considered, particularly for long-term use.
Herbal Products: St. John's wort (Hypericum perforatum)	↓ etravirine	Concomitant use of INTELENCE^® with products containing St. John's wort may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE^®. INTELENCE^® and products containing St. John's wort should not be co-administered.
HMG-CoA Reductase Inhibitors: atorvastatin fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin	↔ etravirine ↓ atorvastatin ↑ 2-OH-atorvastatin ↔ etravirine ↑ fluvastatin, ↓ lovastatin, ↑ pitavastatin, ↔ pravastatin, ↔ rosuvastatin, ↓ simvastatin	The combination of INTELENCE^® and atorvastatin can be given without dose adjustments, however, the dose of atorvastatin may need to be altered based on clinical response. No interaction between pravastatin, rosuvastatin and INTELENCE^® is expected. Lovastatin and simvastatin are CYP3A substrates and co-administration with INTELENCE^® may result in lower plasma concentrations of the HMG-CoA reductase inhibitor. Fluvastatin and pitavastatin are metabolized by CYP2C9 and co-administration with INTELENCE^® may result in higher plasma concentrations of the HMG-CoA reductase inhibitor. Dose adjustments for these HMG-CoA reductase inhibitors may be necessary.
Immunosuppressants: cyclosporine, sirolimus, tacrolimus	↓ immunosuppressant	INTELENCE^® and systemic immunosuppressants should be co-administered with caution because plasma concentrations of cyclosporine, sirolimus, or tacrolimus may be affected.
Narcotic Analgesics/Treatment of Opioid Dependence: buprenorphine, buprenorphine/naloxone, methadone	↔ etravirine ↓ buprenorphine ↔ norbuprenorphine ↔ methadone	INTELENCE^® and buprenorphine (or buprenorphine/naloxone) can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as buprenorphine (or buprenorphine/naloxone) maintenance therapy may need to be adjusted in some patients. INTELENCE^® and methadone can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as methadone maintenance therapy may need to be adjusted in some patients.
Phosphodiesterase Type 5 (PDE-5) Inhibitors: sildenafil, tadalafil, vardenafil	↓ sildenafil ↓ N-desmethyl-sildenafil	INTELENCE^® and sildenafil can be co-administered without dose adjustments, however, the dose of sildenafil may need to be altered based on clinical effect.
Platelet Aggregation Inhibitors: clopidogrel	↓ clopidogrel (active) metabolite	Activation of clopidogrel to its active metabolite may be decreased when clopidogrel is co-administered with INTELENCE^®. Alternatives to clopidogrel should be considered.

Table name:

Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, gemfibrozil, cyclosporine,danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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CYP2C19 or CYP3A4 Inducers
Clinical Impact:	Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention:	St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions (5.9)]. Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:	Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
Intervention:	Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole.

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Table 13. Established and Other Potentially Significant Drug Interactions
↓= Decreased (induces lamotrigine gluronidation). ↑= Increased (inhibits lamotrigine gluronidation). ?= Conflicting data.
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine ? CBZ epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 4: Clinically Significant Drug Interactions with OXYCONTIN
Inhibitors of CYP3A4 and CYP2D6
Clinical Impact:	The concomitant use of OXYCONTIN and CYP3A4 inhibitors can increase the plasma concentration of oxycodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of OXYCONTIN and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of OXYCONTIN is achieved [see Warnings and Precautions (5.4)]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the oxycodone plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to oxycodone.
Intervention:	If concomitant use is necessary, consider dosage reduction of OXYCONTIN until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the OXYCONTIN dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact:	The concomitant use of OXYCONTIN and CYP3A4 inducers can decrease the plasma concentration of oxycodone [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to oxycodone [see Warnings and Precautions (5.4)]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the oxycodone plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention: Examples:	If concomitant use is necessary, consider increasing the OXYCONTIN dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider OXYCONTIN dosage reduction and monitor for signs of respiratory depression. Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Dosage and Administration (2.6), Warnings and Precautions (5.5)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue OXYCONTIN if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
Intervention:	The use of OXYCONTIN is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of OXYCONTIN and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Oxycodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of OXYCONTIN and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when OXYCONTIN is used concomitantly with anticholinergic drugs.

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Interacting Drug	Interaction
Drugs known to prolong QT interval (e.g., Class IA and Class III antiarrhythmic agents).	Quinine sulfate prolongs QT interval, ECG abnormalities including QT prolongation and torsade de pointes. Avoid concomitant use (5.3).
Other antimalarials (e.g., halofantrine, mefloquine).	ECG abnormalities including QT prolongation. Avoid concomitant use (5.3, 7.2).
CYP3A4 inducers or inhibitors	Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine (7.1).
CYP3A4 and CYP2D6 substrates	Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the coadministered drug (7.2).
Digoxin	Increased digoxin plasma concentration (5.8, 7.1).

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name:

Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, gemfibrozil, cyclosporine,danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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NA – Not available/reported
Digoxin concentrations increased greater than 50%
	Digoxin Serum Concentration Increase	Digoxin AUC Increase	Recommendations
Amiodarone	70%	NA	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
Captopril	58%	39%
Clarithromycin	NA	70%
Dronedarone	NA	150%
Gentamicin	129-212%	NA
Erythromycin	100%	NA
Itraconazole	80%	NA
Nitrendipine	57%	15%
Propafenone	NA	60-270%
Quinidine	100%	NA
Ranolazine	50%	NA
Ritonavir	NA	86%
Tetracycline	100%	NA
Verapamil	50-75%	NA
Digoxin concentrations increased less than 50%
Atorvastatin	22%	15%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
Carvedilol	16%	14%
Diltiazem	20%	NA
Indomethacin	40%	NA
Nefazodone	27%	15%
Nifedipine	45%	NA
Propantheline	24%	24%
Quinine	NA	33%
Saquinavir	27%	49%
Spironolactone	25%	NA
Telmisartan	20-49%	NA
Tolvaptan	30%	NA
Trimethoprim	22-28%	NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole, rabeprazole,			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate, sulfasalazine			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20-40% as necessary.
No significant Digoxin exposure changes
Please refer to section 12 for a complete list of drugs which were studied but reported no significant changes on digoxin exposure.			No additional actions are required.

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Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate. [See Warnings and Precautions (5.9).]
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.11) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [See Adverse Reactions (6.1).]
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions (5.16)].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies in and postmarketing.
Sildenafil	Use with caution Two-fold increase in exposure	Monitor for sildenafil toxicity (see Clinical Pharmacology (12.3)].
Duloxetine	Avoid Use Five-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx^®(didanosine) chewable/ buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2.4)].	Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin	Monitor phenytoin level (7)
Methotrexate	Monitor for methotrexate toxicity (7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)

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Table 18. Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9- Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Co-administered Drug	Dosing Schedule		Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference)		Risperidone Dose Recommendation
	Co-administered Drug	Risperidone	AUC	C_max
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Table 4 Other Potentially Significant Drug Interactions
Concomitant Drug Class or Food	Noted or Anticipated Outcome	Clinical Comment
HMG-Co A Reductase Inhibitors: atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin	Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality) P-gp substrate; rhabdomyolysis has been reported	Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy.
Other Lipid-Lowering Drugs: fibrates, gemfibrozil
Digitalis Glycosides: digoxin

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
↓= Decreased (induces lamotrigine gluronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ?= Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
	? CBZ epoxide	May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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I. Due to the competition of salicylate with other drugs for binding to serum albumin the following drug interactions may occur:
DRUG	DESCRIPTION OF INTERACTION
Sulfonylureas	Hypoglycemia potentiated.
Methotrexate	Decreases tubular reabsorption; clinical toxicity from methotrexate can result.
Oral Anticoagulants	Increased bleeding.
II. Drugs changing salicylate levels by altering renal tubular reabsorption:
DRUG	DESCRIPTION OF INTERACTION
Corticosteroids	Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents	Increases plasma salicylate levels.
Alkanizing Agents	Decreased plasma salicylate levels.
III. Drugs with complicated interactions with salicylates:
DRUG	DESCRIPTION OF INTERACTION
Heparin	Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients.
Pyrazinamide	Inhibits pyrazinamide-induced hyperuricemia.
Uricosuric Agents	Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.
The following alterations of laboratory tests have been reported during salicylate therapy:
LABORATORY TESTS	EFFECT OF SALICYLATES
Thyroid Function	Decreased PBI; increased t₃ uptake.
Urinary Sugar	False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.).
5-Hydroxyindole acetic acid	False negative with fluorometric test.
Acetone ketone bodies	False positive FeCI₃ in Gerhardt reaction; red color persists with boiling.
17-OH corticosteroids	False reduced values with >4.8g q.d. salicylate.
Vanilmandelic acid	False reduced values.
Uric Acid	May increase or decrease depending on dose.
Prothrombin	Decreased levels; slightly increased prothrombin time.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Table IIl Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
* Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol, systemic and inhaled	hydrocortisone	nizatidine
amoxicillin	isoflurane	norfloxacin
ampicillin, with or without sulbactam	isoniazid	ofloxacin
atenolol	isradipine	omeprazole
azithromycin	influenza vaccine	prednisone, prednisolone
caffeine, dietary ingestion	ketoconazole	ranitidine
cefaclor	lomefloxacin	rifabutin
co-trimoxazole	mebendazole	roxithromycin
(trimethoprim and sulfamethoxazole) diltiazem	medroxyprogesterone	sorbitol
dirithromycin	methylprednisolone	(purgative doses do not inhibit theophylline absorption)
enflurane	metronidazole	sucralfate
famotidine	metoprolol	terbutaline, systemic
felodipine	nadolol	terfenadine
finasteride	nifedipine	tetracycline tocainide

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Drugs That Interfere with Hemostasis
Clinical Impact:	Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of indomethacin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions ( 5.11 )].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions ( 5.2 ) ].
Intervention:	Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions ( 5.11 )].Indomethacin is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of indomethacin capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.During concomitant use of indomethacin capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions ( 5.6 )].When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.It has been reported that the addition of triamterene to a maintenance schedule of Indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together.Both indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently [ see Warnings and Precautions ( 5.6 )].
Intervention:	Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels. [ see Warnings and Precautions ( 5.6 )].
Digoxin
Clinical Impact:	The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention:	During concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions ( 5.2 )]. Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin [see Clinical Pharmacology ( 12.3 )].In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage.
Intervention:	The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Probenecid
Clinical Impact:	When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased.
Intervention:	During the concomitant use of indomethacin and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments.

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
*Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol, systemic and inhaled	hydrocortisone	nizatidine
amoxicillin	isoflurane	norfloxacin
ampicillin, with or without sulbactam	isoniazid	ofloxacin
atenolol	isradipine	omeprazole
azithromycin	influenza vaccine	prednisone, prednisolone
caffeine, dietary ingestion	ketoconazole	ranitidine
cefaclor	lomefloxacin	rifabutin
co-trimoxazole (trimethoprim and sulfamethoxazole)	mebendazole	roxithromycin
diltiazem	medroxyprogesterone	sorbitol (purgative doses do not inhibit
dirithromycin	methylprednisolone	theophylline absorption)
enflurane	metronidazole	sucralfate
famotidine	metoprolol	terbutaline, systemic
felodipine	nadolol	terfenadine
finasteride	nifedipine	tetracycline
		tocainide

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Drugs That Interfere with Hemostasis
Clinical Impact:	Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of celecoxib capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions (5.11) ].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions (5.2) ]. In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200-400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100-325 mg).
Intervention:	Concomitant use of celecoxib capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions (5.11) ]. Celecoxib capsules are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of celecoxib capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of celecoxib capsules and ACE-inhibitors or ARBs in patients who are elderly, volume- depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions (5.6) ]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of celecoxib capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see Warnings and Precautions (5.6) ].
Digoxin
Clinical Impact:	The concomitant use of celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of celecoxib capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of celecoxib capsules and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Celecoxib capsules have no effect on methotrexate pharmacokinetics.
Intervention:	During concomitant use of celecoxib capsules and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of celecoxib capsules and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of celecoxib capsules and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions (5.2) ].
Intervention:	The concomitant use of celecoxib with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of celecoxib capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of celecoxib capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or inducers
Clinical Impact:	Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib.
Intervention	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers [ see Clinical Pharmacology (12.3) ].
CYP2D6 substrates
Clinical Impact:	In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs.
Intervention	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates [ see Clinical Pharmacology (12.3) ].
Corticosteroids
Clinical Impact:	Concomitant use of corticosteroids with celecoxib capsules may increase the risk of GI ulceration or bleeding.
Intervention	Monitor patients with concomitant use of celecoxib capsules with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)].

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name:

CYP2C19 or CYP3A4 Inducers
Clinical Impact:	Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention:	St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions (5.9)]. Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:	Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
Intervention:	Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole.

Table name:

LABORATORY TESTS	EFFECT OF SALICYLATES
Thyroid Function	Decreased PBI; increased T₃ uptake.
Urinary Sugar	False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.).
5-Hydroxyindole acetic acid	False negative with fluorometric test.
Acetone, ketone bodies	False positive FeCl₃ in Gerhardt reaction; red color persists with boiling.
17-OH corticosteroids	False reduced values with >4.8g q.d. salicylate.
Vanilmandelic acid	False reduced values.
Uric acid	May increase or decrease depending on dose.
Prothrombin	Decreased levels; slightly increased prothrombin time.

Table name:

Bleeding times
Clinical Impact:	Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention:	This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact:	The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention:	Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact:	Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention:	This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.

Table name:

Name of the Concomitant Drug	Change in the Concentration of Ganciclovir or Concomitant Drug	Clinical Comment
Zidovudine	↓ Ganciclovir ↑ Zidovudine	Zidovudine and valganciclovir tablets each have the potential to cause neutropenia and anemia
Probenicid	↑ Ganciclovir	Patients taking probenicid and valganciclovir tablets should be monitored for evidence of ganciclovir toxicity
Mycophenolate Mofetil (MMF)	↔ Ganciclovir (in patients with normal renal function) ↔ MMF (in patients with normal renal function)	Patients with renal impairment should be monitored carefully as levels of MMF metabolites and ganciclovir may increase
Didanosine	↓ Ganciclovir ↑ Didanosine	Patients should be closely monitored for didanosine toxicity

Table name:

Table 2: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 5 mg in BPH patients on stable alpha-blocker therapy (Study 1)
Alpha-Blocker		Simultaneous dosing of Vardenafil 5 mg and Alpha-Blocker, Placebo-Subtracted	Dosing of Vardenafil 5 mg and Alpha-Blocker Separated by 6 Hours, Placebo-Subtracted
Terazosin 5 or 10 mg daily	Standing SBP	-3 (-6.7, 0.1)	-4 (-7.4, -0.5)
Terazosin 5 or 10 mg daily	Supine SBP	-4 (-6.7, -0.5)	-4 (-7.1, -0.7)
Tamsulosin 0.4 mg daily	Standing SBP Supine SBP	-6 (-9.9, -2.1) -4 (-7.0, -0.8)	-4 (-8.3, -0.5) -5 (-7.9, -1.7)

Table name:

CONCOMITANT DRUG	CLINICAL EFFECT(S)
Amphetamines, cocaine, other sympathomimetic agents	Additive hypertension, tachycardia, possibly cardiotoxicity
Atropine, scopolamine, antihistamines, other anticholinergic agents	Additive or super-additive tachycardia, drowsiness
Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants	Additive tachycardia, hypertension, drowsiness
Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants	Additive drowsiness and CNS depression
Disulfiram	A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge
Fluoxetine	A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days
Antipyrine, barbiturates	Decreased clearance of these agents,presumably via competitive inhibition of metabolism
Theophylline	Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco

Table name:

Table 8: Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C_max and AUC_τ)	Recommendations for Drug Dosage Adjustment/Comments
SirolimusResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (400 mg q24h)Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (300 mg q24h) (CYP3A4 Inhibition)	Slight Increase in AUC_τ	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)(CYP3A4 Inhibition)	No Significant Effect of Voriconazole on Ritonavir C_max or AUC_τ	Contraindicated because of significant reduction of voriconazole C_max and AUC_τ

Low-dose Ritonavir (100 mg q12h)	Slight Decrease in Ritonavir C_max and AUC_τ	Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole C_max and AUC_τ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated
Cyclosporine (CYP3A4 Inhibition)	AUC_τ Significantly Increased; No Significant Effect on C_max	When initiating therapy with VFEND in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When VFEND is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
MethadoneResults based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30–100 mg q24h) (CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7)]
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with VFEND. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see Drug Interactions (7)].
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with VFEND. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7)].
NSAIDsNon-Steroidal Anti-Inflammatory Drug including. ibuprofen and diclofenac (CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [see Drug Interactions (7)].
Tacrolimus (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When VFEND is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)	Increased	Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with VFEND in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects on Indinavir Exposure	No dosage adjustment for indinavir when coadministered with VFEND
	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.
Everolimus (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Concomitant administration of voriconazole and everolimus is not recommended.

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( 2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents	Carefully monitor blood glucose ( 5.12, 7.3)

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

Table name:

Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.

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Table 7: Summary of AED Interactions with Oxcarbazepine
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400 to 2,000	900	ncnc denotes a mean change of less than 10%	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100 to 150	600 to 1,800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250 to 500	600 to 1,800 >1,200 to 2,400	nc Pediatrics up to 40% increaseMean increase in adults at high oxcarbazepine doses [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400 to 2,800	600 to 1,800	nc	18% decrease [CI: 13% decrease, 40% decrease]

Table name: Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of Celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.During concomitant use of celecoxib and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of celecoxib and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6) ]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.

Table 3: Clinically Significant Drug Interactions with Celecoxib
Drugs That Interfere with Hemostasis
Clinical Impact:
Intervention:	Monitor patients with concomitant use of celecoxib with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11) ].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2) ]. In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200 to 400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100 to 325 mg).
Intervention:	Concomitant use of celecoxib and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11) ]. Celecoxib is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:
Intervention:
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of celecoxib with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6) ].
Digoxin
Clinical Impact:	The concomitant use of Celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of celecoxib and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of celecoxib and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Celecoxib has no effect on methotrexate pharmacokinetics.
Intervention:	During concomitant use of celecoxib and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of celecoxib and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of celecoxib and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2) ].
Intervention:	The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of celecoxib and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of celecoxib and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or inducers
Clinical Impact:	Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co‑-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib.
Intervention	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [see Clinical Pharmacology (12.3) ].
CYP2D6 substrates
Clinical Impact:	In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs.
Intervention	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [see Clinical Pharmacology (12.3) ].
Corticosteroids
Clinical Impact:	Concomitant use of corticosteroids with celecoxib may increase the risk of GI ulceration or bleeding.
Intervention	Monitor patients with concomitant use of celecoxib with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2) ].

Table name:

Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( 7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( 7)
Phenytoin	Monitor phenytoin level ( 7)
Methotrexate	Monitor for methotrexate toxicity ( 7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine ( 7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased Ciprofloxacin Tablets, USP absorption. Take 2 hours before or 6 hours after Ciprofloxacin Tablets, USP ( 7)

Table name:

Table 3: Clinically Relevant Interactions Affecting Drugs Co-Administered with Omeprazole and Interaction with Diagnostics
Antiretrovirals
Clinical Impact:	The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3)]. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)]. There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
Intervention:	Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications (4) ]. Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:	Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention:	Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact:	Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11) ].
Intervention:	A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact:	Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3) ]. There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention:	Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6) ].
Citalopram
Clinical Impact:	Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3) ].
Intervention:	Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:	Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3) ].
Intervention:	Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:	Potential for increased exposure of phenytoin.
Intervention:	Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:	Increased exposure of diazepam [see Clinical Pharmacology (12.3) ].
Intervention:	Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:	Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3) ].
Intervention:	Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:	Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:	Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3) ]. See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:	Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:	See Contraindications , Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact:	Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention:	Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:	Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10) , Clinical Pharmacology (12.2) ].
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:	Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact:	There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:	An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:	There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:	Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.

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Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs that Interfere with Hemostasis
Clinical Impact :	Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention :	Monitor patients with concomitant use of Meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact :	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention :	Concomitant use of Meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors , Angiotensin Receptor Blockers , or Beta - Blockers
Clinical Impact :	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention :	During concomitant use of Meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of Meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact :	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention :	During concomitant use of Meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Lithium
Clinical Impact :	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology (12.3)].
Intervention :	During concomitant use of Meloxicam and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact :	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention :	During concomitant use of Meloxicam and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact :	Concomitant use of Meloxicam and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention :	During concomitant use of Meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact :	Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention :	The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact :	Concomitant use of Meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention :	During concomitant use of Meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.

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Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
*Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	Cmax
Enzyme (CYP2D6) inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not Needed

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Table 7 Summary of AED Interactions with Oxcarbazepine
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400-2000	900	ncnc denotes a mean change of less than 10%	40% decrease [CI: 17% decrease,57% decrease]
Phenobarbital	100-150	600-1800	14% increase[CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease,51% decrease]
Phenytoin	250-500	600-1800>1200-2400	nc up to 40% increase [CI: 12% increase,60% increase]	30% decrease [CI: 3% decrease,48% decrease]
Valproic acid	400-2800	600-1800	nc	18% decrease [CI: 13% decrease,40% decrease]

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 18 Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Co-administered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
	Co-administered Drug	Risperidone	AUC	C_max
Enzyme (CYP2D6)Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-	Re-evaluate dosing. Do not exceed 8 mg/day
Enzyme (CYP3A/PgP inducers)Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A)Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed

Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Figure 1: Effect of interacting drugs on the pharmacokinetics of venlafaxine and active metabolite O-desmethylvenlafaxine (ODV).

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CONCOMITANT DRUG	CLINICAL EFFECT(S)
Amphetamines, cocaine, other sympathomimetic agents	Additive hypertension, tachycardia, possibly cardiotoxicity
Atropine, scopolamine, antihistamines, other anticholinergic agents	Additive or super-additive tachycardia, drowsiness
Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants	Additive tachycardia, hypertension, drowsiness
Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants	Additive drowsiness and CNS depression
Disulfiram	A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge
Fluoxetine	A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days
Antipyrine, barbiturates	Decreased clearance of these agents, presumably via competitive inhibition of metabolism
Theophylline	Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco

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Table 9 Established and Other Potentially Significant Drug Interactions With Ganciclovir
Name of the Concomitant Drug	Change in the Concentration of Ganciclovir or Concomitant Drug	Clinical Comment
Zidovudine	↓ Ganciclovir ↑ Zidovudine	Zidovudine and valganciclovir each have the potential to cause neutropenia and anemia
Probenecid	↑ Ganciclovir	Patients taking probenecid and valganciclovir should be monitored for evidence of ganciclovir toxicity
Mycophenolate Mofetil (MMF)	↔ Ganciclovir (in patients with normal renal function) ↔ MMF (in patients with normal renal function)	Patients with renal impairment should be monitored carefully as levels of MMF metabolites and ganciclovir may increase
Didanosine	↓ Ganciclovir ↑ Didanosine	Patients should be closely monitored for didanosine toxicity

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Table 7: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (C_max and AUC_τ after 200 mg q12h)	Recommendations for Voriconazole Dosage Adjustment/Comments
RifampinResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects and Rifabutin (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (400 mg q24h)Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects (CYP450 Induction)	Significantly Reduced	Contraindicated

Efavirenz (300 mg q24h) (CYP450 Induction)	Slight Decrease in AUC _τ	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h) (CYP450 Induction)	Significantly Reduced	Contraindicated
Low-dose Ritonavir (100 mg q12h) (CYP450 Induction)	Reduced	Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Phenytoin (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John's Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir

	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to voriconazole

	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Careful assessment of voriconazole effectiveness

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Drugs That Interfere with Hemostasis
Clinical Impact:	• Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	• During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

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CONCOMITANT DRUG	CLINICAL EFFECT(S)
Amphetamines, cocaine, other sympathomimetic agents	Additive hypertension, tachycardia, possibly cardiotoxicity
Atropine, scopolamine, antihistamines, other anticholinergic agents	Additive or super-additive tachycardia, drowsiness
Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants	Additive tachycardia, hypertension, drowsiness
Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants	Additive drowsiness and CNS depression
Disulfiram	A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge
Fluoxetine	A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days
Antipyrine, barbiturates	Decreased clearance of these agents, presumably via competitive inhibition of metabolism
Theophylline	Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco
Opioids	Cross-tolerance and mutual potentiation
Naltrexone	Oral THC effects were enhanced by opioid receptor blockade.
Alcohol	Increase in the positive subjective mood effects of smoked marijuana

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NA – Not available/reported
Digoxin concentrations increased greater than 50%
	Digoxin Serum Concentration Increase	Digoxin AUC Increase	Recommendations
Amiodarone	70%	NA	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
Captopril	58%	39%
Clarithromycin	NA	70%
Dronedarone	NA	150%
Gentamicin	129-212%	NA
Erythromycin	100%	NA
Itraconazole	80%	NA
Nitrendipine	57%	15%
Propafenone	NA	60-270%
Quinidine	100%	NA
Ranolazine	50%	NA
Ritonavir	NA	86%
Tetracycline	100%	NA
Verapamil	50-75%	NA
Digoxin concentrations increased less than 50%
Atorvastatin	22%	15%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
Carvedilol	16%	14%
Diltiazem	20%	NA
Indomethacin	40%	NA
Nefazodone	27%	15%
Nifedipine	45%	NA
Propantheline	24%	24%
Quinine	NA	33%
Saquinavir	27%	49%
Spironolactone	25%	NA
Telmisartan	20-49%	NA
Tolvaptan	30%	NA
Trimethoprim	22-28%	NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole, rabeprazole,			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate, sulfasalazine			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20-40% as necessary.
No significant Digoxin exposure changes
Please refer to section 12 for a complete list of drugs which were studied but reported no significant changes on digoxin exposure.			No additional actions are required.

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Table 6: Clinically Significant Drug Interactions with BASAGLAR
Drugs That May Increase the Risk of Hypoglycemia
Drugs:	Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics.
Intervention:	Dose reductions and increased frequency of glucose monitoring may be required when BASAGLAR is co-administered with these drugs.
Drugs That May Decrease the Blood Glucose Lowering Effect of BASAGLAR
Drugs:	Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones
Intervention:	Dose increases and increased frequency of glucose monitoring may be required when BASAGLAR is co-administered with these drugs.
Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of BASAGLAR
Drugs:	Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.
Intervention:	Dose adjustment and increased frequency of glucose monitoring may be required when BASAGLAR is co-administered with these drugs.
Drugs That May Blunt Signs and Symptoms of Hypoglycemia
Drugs:	beta-blockers, clonidine, guanethidine, and reserpine
Intervention:	Increased frequency of glucose monitoring may be required when BASAGLAR is co-administered with these drugs.

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Table 4: Clinically Significant Drug Interactions with OXYCONTIN
Inhibitors of CYP3A4 and CYP2D6
Clinical Impact:	The concomitant use of OXYCONTIN and CYP3A4 inhibitors can increase the plasma concentration of oxycodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of OXYCONTIN and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of OXYCONTIN is achieved [see Warnings and Precautions (5.4)]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the oxycodone plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to oxycodone.
Intervention:	If concomitant use is necessary, consider dosage reduction of OXYCONTIN until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the OXYCONTIN dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact:	The concomitant use of OXYCONTIN and CYP3A4 inducers can decrease the plasma concentration of oxycodone [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to oxycodone [see Warnings and Precautions (5.4)]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the oxycodone plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention: Examples:	If concomitant use is necessary, consider increasing the OXYCONTIN dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider OXYCONTIN dosage reduction and monitor for signs of respiratory depression. Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Dosage and Administration (2.6), Warnings and Precautions (5.5)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue OXYCONTIN if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
Intervention:	The use of OXYCONTIN is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of OXYCONTIN and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Oxycodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of OXYCONTIN and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when OXYCONTIN is used concomitantly with anticholinergic drugs.

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Beta-Blockers
Clinical Impact:	The concomitant use of beta-blockers and Glucagon for Injection may increase the risk of a temporary increase in heart rate and blood pressure.
Intervention:	The increase in blood pressure and heart rate may require therapy in patients with coronary artery disease.
Insulin
Clinical Impact:	Insulin reacts antagonistically towards glucagon.
Intervention:	Monitor blood glucose when Glucagon for Injection is used as a diagnostic aid in diabetes patients.
Indomethacin
Clinical Impact:	The concomitant use of indomethacin and Glucagon for Injection may lead to hypoglycemia.
Intervention:	Monitor blood glucose levels during glucagon treatment of patients taking indomethacin.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs and Glucagon for Injection increase the risk of gastrointestinal adverse reactions due to additive effects on inhibition of gastrointestinal motility.
Intervention:	Concomitant use is not recommended.
Warfarin
Clinical Impact:	Glucagon may increase the anticoagulant effect of warfarin.
Intervention:	Monitor patients for unusual bruising or bleeding, as adjustments in warfarin dosage may be required.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium ( 2.4 , 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents	Carefully monitor blood glucose ( 5.12 , 7.3)

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Factors	Dosage Adjustments for Aripiprazole
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors	Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double usual dose over 1 to 2 weeks

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Bleeding times
Clinical Impact:	Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention:	This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact:	The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention:	Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact:	Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention:	This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 18. Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9- Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Co-administered Drug	Dosing Schedule		Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference)		Risperidone Dose Recommendation
	Co-administered Drug	Risperidone	AUC	C_max
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Table 13. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation). ↑ = Increased (inhibits lamotrigine glucuronidation). ? = Conflicting data.
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C_max and AUC_τ)	Recommendations for Drug Dosage Adjustment/Comments
Sirolimus^* (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin^* (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (400 mg q24h)^† (CYP450 Induction) Efavirenz (300 mg q24h)^† (CYP450 Induction)	Significantly Increased Slight Increase in AUC_τ	Contraindicated When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High dose Ritonavir (400 mg q12h)^†(CYP3A4 Inhibition) Low dose Ritonavir (100 mg q12h)^†	No Significant Effect of Voriconazole on Ritonavir C_max or AUC_τ Slight Decrease in Ritonavir C_max and AUC_τ	Contraindicated because of significant reduction of voriconazole C_max and AUC_τ Coadministration of voriconazole and low dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole C_max and AUC_τ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated
Cyclosporine^* (CYP3A4 Inhibition)	AUCτ Significantly Increased; No Significant Effect on C_max	When initiating therapy with voriconazole in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
Methadone^‡ (CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7) ]
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see Drug Interactions (7) ].
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7) ].
NSAIDs ^§ including. ibuprofen and diclofenac (CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [see Drug Interactions (7) ].
Tacrolimus^* (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with voriconazole in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin^* (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)^†	Increased	Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin^* (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole^* (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with voriconazole in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects on Indinavir Exposure In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	No dosage adjustment for indinavir when coadministered with voriconazole Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIs ^¶ (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.
Everolimus (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Concomitant administration of voriconazole and everolimus is not recommended.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4 , 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11 , 7.3)

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Interacting Drug	Interaction
Drugs known to prolong QT interval (e.g., Class IA and Class III anti-arrhythmic agents).	Quinine Sulfate Capsules prolong QT interval, ECG abnormalities including QT prolongation and Torsades de Pointes. Avoid concomitant use (5.3).
Other antimalarials (e.g., halofantrine, mefloquine).	ECG abnormalities including QT prolongation. Avoid concomitant use (5.3, 7.2).
CYP3A4 inducers or inhibitors	Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine (7.1).
CYP3A4 and CYP2D6 substrates	Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the co-administered drug (7.2).
Digoxin	Increased digoxin plasma concentration (5.8, 7.1).

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NA – Not available/reported
Digoxin concentrations increased greater than 50%
	Digoxin Serum Concentration Increase	Digoxin AUC Increase	Recommendations
Amiodarone	70%	NA	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30% to 50% or by modifying the dosing frequency and continue monitoring.
Captopril	58%	39%
Clarithromycin	NA	70%
Dronedarone	NA	150%
Gentamicin	129% to 212%	NA
Erythromycin	100%	NA
Itraconazole	80%	NA
Lapatinib	NA	180%
Nitrendipine	57%	15%
Propafenone	NA	60% to 270%
Quinidine	100%	NA
Ranolazine	50%	NA
Ritonavir	NA	86%
Telaprevir	50%	85%
Tetracycline	100%	NA
Verapamil	50% to 75%	NA
Digoxin concentrations increased less than 50%
Atorvastatin	22%	15%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15% to 30% or by modifying the dosing frequency and continue monitoring.
Carvedilol	16%	14%
Conivaptan	33%	43%
Diltiazem	20%	NA
Indomethacin	40%	NA
Nefazodone	27%	15%
Nifedipine	45%	NA
Propantheline	24%	24%
Quinine	NA	33%
Rabeprazole	29%	19%
Saquinavir	27%	49%
Spironolactone	25%	NA
Telmisartan	20% to 49%	NA
Ticagrelor	31%	28%
Tolvaptan	30%	NA
Trimethoprim	22% to 28%	NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate and sulfasalazine			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20% to 40% as necessary.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.12, 7.3)

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Table 2: Clinically Relevant Interactions Affecting Drugs Co-Administered with Rabeprazole Sodium Delayed-Release Tablets
Antiretrovirals
Clinical Impact:	The effect of PPI on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and nelfinavir) when used concomitantly with rabeprazole may reduce antiviral effect and promote the development of drug resistance. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with rabeprazole may increase toxicity. There are other antiretroviral drugs which do not result in clinically relevant interactions with rabeprazole.
Intervention:	Rilpivirine-containing products: Concomitant use with rabeprazole sodium rabeprazole sodium delayed-release tablets is contraindicated [see Contraindications (4)]. See prescribing information. Atazanavir: See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with rabeprazole sodium delayed-release tablets. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir and monitor for potential saquinavir toxicities. Other antiretrovirals: See prescribing information.
Warfarin
Clinical Impact:	Increased INR and prothrombin time in patients receiving PPIs, including rabeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death [see Warnings and Precautions (5.2)].
Intervention:	Monitor INR and prothrombin time. Dose adjustment of warfarin may be needed to maintain target INR range. See prescribing information for warfarin.
Methotrexate
Clinical Impact:	Concomitant use of rabeprazole with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of methotrexate with PPIs have been conducted [see Warnings and Precautions (5.9)].
Intervention:	A temporary withdrawal of rabeprazole sodium delayed-release tablets may be considered in some patients receiving high dose methotrexate administration.
Digoxin
Clinical Impact:	Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention:	Monitor digoxin concentrations. Dose adjustment of digoxin may be needed to maintain therapeutic drug concentrations. See prescribing information for digoxin.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole, itraconazole)
Clinical Impact:	Rabeprazole can reduce the absorption of drugs due to its effect on reducing intragastric acidity.
Intervention:	Mycophenolate mofetil (MMF): Co-administration of PPIs in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving PPIs and MMF. Use rabeprazole sodium delayed-release tablets with caution in transplant patients receiving MMF. See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:	Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:	See Contraindications and Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
↓= Decreased (induces lamotrigine glucuronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ? = Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine (CBZ) and CBZ epoxide	? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine concentrations approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine and carbamazepine epoxide	? carbamazepine epoxide	May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Table 3: Clinically Relevant Interactions Affecting Drugs Co-Administered with Omeprazole and Interaction with Diagnostics
Antiretrovirals
Clinical Impact:	The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology ( 12.3)]. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)]. There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
Intervention:	Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications ( 4)] . Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:	Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention:	Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact:	Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions ( 5.11)].
Intervention:	A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact:	Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology ( 12.3)]. There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel .
Intervention:	Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions ( 5.6)].
Citalopram
Clinical Impact:	Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology ( 12.3)] .
Intervention:	Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:	Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology ( 12.3)].
Intervention:	Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:	Potential for increased exposure of phenytoin.
Intervention:	Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:	Increased exposure of diazepam [see Clinical Pharmacology ( 12.3)] .
Intervention:	Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:	Potential for increased exposure of digoxin [see Clinical Pharmacology ( 12.3)].
Intervention:	Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:	Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:	Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology ( 12.3)] . See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:	Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:	See Contraindications, Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact:	Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19 .
Intervention:	Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:	Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions ( 5.10), Clinical Pharmacology ( 12.2)] .
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:	Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology ( 12.2)] .
False Positive Urine Tests for THC
Clinical Impact:	There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:	An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:	There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:	Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine, danazol	Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem	Do not exceed 40 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Drugs That Interfere with Hemostasis
Clinical Impact:	• Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of naproxen delayed-release tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity ).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	Concomitant use of naproxen delayed-release tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen delayed-release tablets are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	• During concomitant use of naproxen delayed-release tablets and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen delayed-release tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention	During concomitant use of naproxen delayed-release tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of naproxen delayed-release tablets and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen delayed-release tablets and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen delayed-release tablets and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen delayed-release tablets and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen delayed-release tablets and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen delayed-release tablets and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of naproxen delayed-release tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen delayed-release tablets is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed-release tablets is not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxen delayed-release tablets is not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen delayed-release tablets and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:	Patients simultaneously receiving naproxen delayed-release tablets and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

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Summary of antiepileptic drug (AED) interactions with topiramate (7.1).
AED co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazaepine (CBZ)	NC	40% decrease
CBZ epoxideIs not administered but is an active metabolite of carbamazepine	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400mg/day	13% decrease

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Table 18. Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9- Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Co-administered Drug	Dosing Schedule		Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference)		Risperidone Dose Recommendation
	Co-administered Drug	Risperidone	AUC	C_max
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Table 2: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 5 mg in BPH patients on stable alpha-blocker therapy (Study 1)
Alpha-Blocker		Simultaneous dosing of Vardenafil 5 mg and Alpha-Blocker, Placebo-Subtracted	Dosing of Vardenafil 5 mg and Alpha-Blocker Separated by 6 Hours, Placebo-Subtracted
Terazosin 5 or 10 mg daily	Standing SBP	-3 (-6.7, 0.1)	-4 (-7.4, -0.5)
Terazosin 5 or 10 mg daily	Supine SBP	-4 (-6.7, -0.5)	-4 (-7.1, -0.7)
Tamsulosin 0.4 mg daily	Standing SBP Supine SBP	-6 (-9.9, -2.1) -4 (-7.0, -0.8)	-4 (-8.3, -0.5) -5 (-7.9, -1.7)

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C Protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitors (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Bleeding times
Clinical Impact:	Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention:	This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact:	The administration of naproxen may result in increased urinary values for 17 ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention:	Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact:	Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention:	This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.

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Table 1. Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of Azithromycin
NA - Not Available ^* - 90% Confidence interval not reported Mean rifabutin concentrations one-half day after the last dose of rifabutin were 60 ng/mL when coadministered with azithromycin and 71 ng/mL when coadministered with placebo.
Coadministered Drug	Dose of Coadministered Drug	Dose of Azithromycin	n	Ratio (with/without azithromycin) of Coadministered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00
Coadministered Drug	Dose of Coadministered Drug	Dose of Azithromycin	n	Mean C_max	Mean AUC
Atorvastatin	10 mg/day x 8 days	500 mg/day PO on days 6 to 8	12	0.83 (0.63 to 1.08)	1.01 (0.81 to 1.25)
Carbamazepine	200 mg/day x 2 days, then 200 mg BID x 18 days	500 mg/day PO for days 16 to 18	7	0.97 (0.88 to 1.06)	0.96 (0.88 to 1.06)
Cetirizine	20 mg/day x 11 days	500 mg PO on day 7, then 250 mg/day on days 8 to 11	14	1.03 (0.93 to 1.14)	1.02 (0.92 to 1.13)
Didanosine	200 mg PO BID x 21 days	1,200 mg/day PO on days 8 to 21	6	1.44 (0.85 to 2.43)	1.14 (0.83 to 1.57)
Efavirenz	400 mg/day x 7 days	600 mg PO on day 7	14	1.04^*	0.95^*
Fluconazole	200 mg PO single dose	1,200 mg PO single dose	18	1.04 (0.98 to 1.11)	1.01 (0.97 to 1.05)
Indinavir	800 mg TID x 5 days	1,200 mg PO on day 5	18	0.96 (0.86 to 1.08)	0.90 (0.81 to 1.00)
Midazolam	15 mg PO on day 3	500 mg/day PO x 3 days	12	1.27 (0.89 to 1.81)	1.26 (1.01 to 1.56)
Nelfinavir	750 mg TID x 11 days	1,200 mg PO on day 9	14	0.90 (0.81 to 1.01)	0.85 (0.78 to 0.93)
Rifabutin	300 mg/day x 10 days	500 mg PO on day 1, then 250 mg/day on days 2 to 10	6	See footnote below	NA
Sildenafil	100 mg on days 1 and 4	500 mg/day PO x 3 days	12	1.16 (0.86 to 1.57)	0.92 (0.75 to 1.12)
Theophylline	4 mg/kg IV on days 1, 11, 25	500 mg PO on day 7, 250 mg/day on days 8 to 11	10	1.19 (1.02 to 1.40)	1.02 (0.86 to 1.22)
Theophylline	300 mg PO BID x 15 days	500 mg PO on day 6, then 250 mg/day on days 7 to 10	8	1.09 (0.92 to 1.29)	1.08 (0.89 to 1.31)
Triazolam	0.125 mg on day 2	500 mg PO on day 1, then 250 mg/day on day 2	12	1.06^*	1.02^*
Trimethoprim/ Sulfamethoxazole	160 mg/800 mg/day PO x 7 days	1,200 mg PO on day 7	12	0.85 (0.75 to 0.97)/0.90 (0.78 to 1.03)	0.87 (0.80 to 0.95)/0.96 (0.88 to 1.03)
Zidovudine	500 mg/day PO x 21 days	600 mg/day PO x 14 days	5	1.12 (0.42 to 3.02)	0.94 (0.52 to 1.70)
Zidovudine	500 mg/day PO x 21 days	1,200 mg/day PO x 14 days	4	1.31 (0.43 to 3.97)	1.30 (0.69 to 2.43)

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Table 6: Clinically Significant Drug Interactions with Paricalcitol
CYP3A Inhibitors
Clinical Impact	Paricalcitol is partially metabolized by CYP3A. Hence, exposure of paricalcitol will increase upon coadministration with strong CYP3A inhibitors such as but not limited to: boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole.
Intervention	Dose adjustment of ZEMPLAR capsules may be necessary. Monitor closely for iPTH and serum calcium concentrations, if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor.
Cholestyramine
Clinical Impact	Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of paricalcitol.
Intervention	Recommend to take ZEMPLAR capsules at least 1 hour before or 4 to 6 hours after taking cholestyramine (or at as great an interval as possible) to avoid impeding absorption of paricalcitol.
Mineral Oil
Clinical Impact	Mineral oil or other substances that may affect absorption of fat may influence the absorption of paricalcitol.
Intervention	Recommend to take ZEMPLAR capsules at least 1 hour before or 4 to 6 hours after taking mineral oil (or at as great an interval as possible) to avoid affecting absorption of paricalcitol.

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Classes of Drugs
5-lipoxygenase Inhibitor Adrenergic Stimulants, Central Alcohol Abuse Reduction Preparations Analgesics Anesthetics, Inhalation Antiandrogen Antiarrhythmics† Antibiotics† Aminoglycosides (oral) Cephalosporins, parenteral Macrolides Miscellaneous Penicillins, intravenous, high dose Quinolones (fluoroquinolones) Sulfonamides, long acting Tetracyclines Anticoagulants Anticonvulsants† Antidepressants† Antimalarial Agents Antineoplastics† Antiparasitic/Antimicrobials	Antiplatelet Drugs/Effects Antithyroid Drugs† Beta-Adrenergic Blockers Cholelitholytic Agents Diabetes Agents, Oral Diuretics† Fungal Medications, Intravaginal, Systemic† Gastric Acidity and Peptic Ulcer Agents† Gastrointestinal Prokinetic Agents Ulcerative Colitis Agents Gout Treatment Agents Hemorrheologic Agents Hepatotoxic Drugs Hyperglycemic Agents Hypertensive Emergency Agents Hypnotics† Hypolipidemics† Bile Acid-Binding Resins† Fibric Acid Derivatives HMG-CoA Reductase Inhibitors†	Leukotriene Receptor Antagonist Monoamine Oxidase Inhibitors Narcotics, prolonged Nonsteroidal Anti- Inflammatory Agents Proton Pump Inhibitors Psychostimulants Pyrazolones Salicylates Selective Serotonin Reuptake Inhibitors Steroids, Adrenocortical† Steroids, Anabolic (17-Alkyl Testosterone Derivatives) Thrombolytics Thyroid Drugs Tuberculosis Agents† Uricosuric Agents Vaccines Vitamins†

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Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)]
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate. [See Warnings and Precautions (5.6).]
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were coadministered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is coadministered with oral antidiabetic drugs. [See Adverse Reactions (6.1).]
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after coadministration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after coadministration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution Two-fold increase in exposure	Monitor for sildenafil toxicity (see Pharmacokinetics 12.3).
Duloxetine	Avoid Use Five-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine	Use with caution	Ciprofloxacin inhibits the formation of paraxanthine after
Derivatives	Reduced clearance resulting in elevated levels and prolongation of serum half-life	caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx^® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation- containing products administration [see Dosage and Administration. (2)].	Decrease ciprofloxacin absorption, resulting in lower serum and urine levels

Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

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Antiarrhythmics	Dofetilide	Concomitant administration with digoxin was associated with a higher rate of torsades de pointes.
Antiarrhythmics	Sotalol	Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
Parathyroid Hormone Analog	Teriparatide	Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid Supplement	Thyroid	Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics	Epinepherine	Can increase the risk of cardiac arrhythmias.
	Norepinephrine
	Dopamine
Neuromuscular Blocking Agents	Succinylcholine	May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements	Calcium	If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic Blockers and Calcium Channel Blockers	Additive effects on AV node conduction can result in complete heart block.
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Blocker	Ivabradine can increase the risk of bradycardia.

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Specific Drugs Reported
also: diet high in vitamin K unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported.
alcohol† aminoglutethimide amobarbital atorvastatin† azathioprine butabarbital butalbital carbamazepine chloral hydrate† chlordiazepoxide chlorthalidone	cholestyramine† clozapine corticotropin cortisone cyclophosphamide† dicloxacillin ethchlorvynol glutethimide griseofulvin haloperidol meprobamate	6-mercaptopurine methimazole† moricizine hydrochloride† nafcillin paraldehyde pentobarbital phenobarbital phenytoin† pravastatin† prednisone† primidone	propylthiouracil† raloxifene ranitidine† rifampin secobarbital spironolactone sucralfate trazodone vitamin C (high dose) vitamin K warfarin underdosage

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Interacting Agent	Examples
Drugs that may increase phenytoin serum levels
Antiepileptic drugs	Ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate
Azoles	Fluconazole, ketoconazole, itraconazole, miconazole, voriconazole
Antineoplastic agents	Capecitabine, fluorouracil
Antidepressants	Fluoxetine, fluvoxamine, sertraline
Gastric acid reducing agents	H₂ antagonists (cimetidine), omeprazole
Sulfonamides	Sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim
Other	Acute alcohol intake, amiodarone, chloramphenicol, chlordiazepoxide, disulfiram, estrogen, fluvastatin, isoniazid, methylphenidate, phenothiazines, salicylates, ticlopidine, tolbutamide, trazodone, warfarin
Drugs that may decrease phenytoin serum levels

Antacids^a	Calcium carbonate, aluminum hydroxide, magnesium hydroxide Prevention or Management: Phenytoin and antacids should not be taken at the same time of day
Antineoplastic agents usually in combination	Bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate
Antiviral agents	Fosamprenavir, nelfinavir, ritonavir
Antiepileptic drugs	Carbamazepine, vigabatrin
Other	Chronic alcohol abuse, diazepam, diazoxide, folic acid, reserpine, rifampin, St. John’s wort^b, sucralfate, theophylline
Drugs that may either increase or decrease phenytoin serum levels
Antiepileptic drugs	Phenobarbital, valproate sodium, valproic acid

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Table 2. Steady-State Plasma Concentrations of Felbamate when Coadministered with Other AEDs
AED Coadministered	AED Concentration	Felbamate Concentration
Phenytoin	↑	↓
Valproate	↑	↔No significant effect.
Carbamazepine (CBZ) Not administered but an active metabolite of carbamazepine.CBZ epoxide	↓ ↑	↓
Phenobarbital	↑	↓

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Table 2: Clinically Significant Drug Interactions with Opana
Alcohol
Clinical Impact:	The concomitant use of alcohol with OPANA can result in an increase of oxymorphone plasma levels and potentially fatal overdose of oxymorphone.
Intervention:	Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while on OPANA therapy [see Clinical Pharmacology (12.3)].
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines and other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue OPANA if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)]. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Intervention:	The use of OPANA is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of OPANA and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Oxymorphone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of OPANA and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when OPANA is used concomitantly with anticholinergic drugs.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when OPANA is used concomitantly with anticholinergic drugs.
Cimetidine
Clinical Impact:	Cimetidine can potentiate opioid-induced respiratory depression.
Intervention:	Monitor patients for respiratory depression when OPANA and cimetidine are used concurrently.

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Table 2: Drug-Thyroidal Axis Interactions
	Drug or Drug Class		Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
		Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
		Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
		Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
		Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
		Amiodarone Iodide (including iodine- containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
	Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
	Drugs that may increase		Drugs that may decrease
	serum TBG concentration		serum TBG concentration
	Clofibrate		Androgens / Anabolic Steroids
	Estrogen-containing oral		Asparaginase
	contraceptives		Glucocorticoids
	Estrogens (oral)		Slow-Release Nicotinic Acid
	Heroin / Methadone
	5-Fluorouracil
	Mitotane
	Tamoxifen
	Drugs that may cause protein-binding site displacement
	Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)		Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
	Carbamazepine Hydantoins Phenobarbital Rifampin		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
	Drugs that may decrease T ₄ 5' - deiodinase activity
	Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)		Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, Ieading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
	Miscellaneous
	Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives		Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
	Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
	Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin		Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
	Cardiac Glycosides		Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
	Cytokines - Interferon-α - Interleukin-2		Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
	Growth Hormones - Somatrem - Somatropin		Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
	Ketamine		Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
	Methylxanthine Bronchodilators - (e.g., Theophylline)		Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
	Radiographic Agents		Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
	Sympathomimetics		Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
	Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics		These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio Change relative to reference)		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	Cmax	Risperidone Dose Recommendation
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Factors	Dosage Adjustment of ABILIFY
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors	Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double usual dose over 1 to 2 weeks

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DRUG INTERACTIONS

CNS depressants: Enhanced CNS-depressant effects with combination use. Use with alcohol causes additive psychomotor impairment (7.1) Imipramine: Decreased alertness observed with combination use. (7.1) Chlorpromazine:Impaired alertness and psychomotor performance observed with combination use (7.1) Rifampin: Combination use decreases exposure to and effects of zolpidem (7.2) Ketoconazole: Combination use increases exposure to and effect of zolpidem (7.2)

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Factors	Dosage Adjustment for Aripiprazole tablets
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors	Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double usual dose over 1 to 2 weeks

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T ₄ and T ₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT ₄. Continued administration results in a decrease in serum T ₄ and normal FT ₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T ₄ and T ₃ to TBG and transthyretin. An initial increase in serum FT ₄, is followed by return of FT ₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T ₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T ₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T ₄ to T ₃, leading to decreased T ₃ levels. However, serum T ₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T ₃ and T ₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T ₃ concentrations by 30% with minimal change in serum T ₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T ₃ and T ₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name:

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Bleeding times
Clinical Impact:	Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention:	This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact:	The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention:	Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact:	Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention:	This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.

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Table 2: Drug-Thyroidal Axis Interactions
	Drug or Drug Class		Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
		Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
		Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
		Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
		Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
		Amiodarone Iodide (including iodine- containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
	Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
	Drugs that may increase		Drugs that may decrease
	serum TBG concentration		serum TBG concentration
	Clofibrate		Androgens / Anabolic Steroids
	Estrogen-containing oral		Asparaginase
	contraceptives		Glucocorticoids
	Estrogens (oral)		Slow-Release Nicotinic Acid
	Heroin / Methadone
	5-Fluorouracil
	Mitotane
	Tamoxifen
	Drugs that may cause protein-binding site displacement
	Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)		Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
	Carbamazepine Hydantoins Phenobarbital Rifampin		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
	Drugs that may decrease T ₄ 5' - deiodinase activity
	Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)		Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, Ieading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
	Miscellaneous
	Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives		Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
	Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
	Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin		Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
	Cardiac Glycosides		Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
	Cytokines - Interferon-α - Interleukin-2		Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
	Growth Hormones - Somatrem - Somatropin		Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
	Ketamine		Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
	Methylxanthine Bronchodilators - (e.g., Theophylline)		Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
	Radiographic Agents		Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
	Sympathomimetics		Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
	Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics		These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 6. Drugs That Should Not Be Coadministered With RESCRIPTOR
Drug Class: Drug Name	Clinical Comment
Anticonvulsant agents: Phenytoin, phenobarbital, carbamazepine	May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of NNRTIs.
Antihistamines: Astemizole, terfenadine	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Antimycobacterials: Rifabutin,^a rifampin^a	May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of NNRTIs or other coadministered antiviral agents.
Ergot Derivatives: Dihydroergotamine, ergonovine, ergotamine, methylergonovine	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
GI motility agent: Cisapride	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Herbal Products: St. John’s wort ( hypericum perforatum)	May lead to loss of virologic response and possible resistance to RESCRIPTOR or to the class of NNRTIs.
HMG-CoA reductase inhibitors: Lovastatin, simvastatin	Potential for serious reactions such as risk of myopathy including rhabdomyolysis.
Neuroleptic: Pimozide	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Sedative/hypnotics: Alprazolam, midazolam, triazolam	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.

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Summary of AED interactions with topiramate (7.1).
AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400mg/day	13% decrease

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

Table name:

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 3: Clinically Significant Drug Interactions with Celecoxib
Drugs That Interfere with Hemostasis
Clinical Impact :	• Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention :	• Monitor patients with concomitant use of celecoxib with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see WARNINGS AND PRECAUTIONS (5.11)].
Aspirin
Clinical Impact :	• Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see WARNINGS AND PRECAUTIONS (5.2)]. In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib capsules (200 to 400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100 to 325 mg).
Intervention :	Concomitant use of celecoxib and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see WARNINGS AND PRECAUTIONS (5.11)]. Celecoxib capsules are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors , Angiotensin Receptor Blockers , and Beta - Blockers
Clinical Impact :	• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention :	• During concomitant use of celecoxib and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of celecoxib and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see WARNINGS AND PRECAUTIONS (5.6)]. • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact :	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention :	During concomitant use of celecoxib with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see WARNINGS AND PRECAUTIONS (5.6)].
Digoxin
Clinical Impact :	The concomitant use of celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention :	During concomitant use of celecoxib and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact :	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention :	During concomitant use of celecoxib and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact :	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Celecoxib capsules has no effect on methotrexate pharmacokinetics.
Intervention :	During concomitant use of celecoxib and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact :	Concomitant use of celecoxib and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention :	During concomitant use of celecoxib and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact :	Concomitant use of celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see WARNINGS AND PRECAUTIONS (5.2)].
Intervention :	The concomitant use of celecoxib with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact :	Concomitant use of celecoxib and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention :	During concomitant use of celecoxib and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or inducers
Clinical Impact :	Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib.
Intervention	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [see CLINICAL PHARMACOLOGY (12.3)].
CYP2D6 substrates
Clinical Impact :	In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs.
Intervention	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [see CLINICAL PHARMACOLOGY (12.3)].
Corticosteroids
Clinical Impact :	Concomitant use of corticosteroids with celecoxib capsules may increase the risk of GI ulceration or bleeding.
Intervention	Monitor patients with concomitant use of celecoxib capsules with corticosteroids for signs of bleeding [see WARNINGS AND PRECAUTIONS (5.2)].

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Table 8: Clinically Significant Drug Interactions with Clarithromycin
Drugs That Are Affected By Clarithromycin
Drug(s) with Pharmacokinetics Affected by Clarithromycin	Recommendation	Comments
Antiarrhythmics: Disopyramide Quinidine Dofetilide Amiodarone Sotalol Procainamide Digoxin	Not Recommended Use With Caution	Disopyramide, Quinidine: There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs [see Warnings and Precautions (5.3)]. Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine. There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide. Digoxin: Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are coadministered, inhibition of Pgp by clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range.
Oral Anticoagulants: Warfarin	Use With Caution	Oral anticoagulants: Spontaneous reports in the postmarketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously [see Warnings and Precautions (5.4)].
Antiepileptics: Carbamazepine	Use With Caution	Carbamazepine: Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered. Increased serum concentrations of carbamazepine were observed in clinical trials with clarithromycin. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with carbamazepine.
Antifungals: Itraconazole Fluconazole	Use With Caution No Dose Adjustment	Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly (see also Itraconazole under “Drugs That Affect Clarithromycin” in the table below). Clarithromycin may increase the plasma concentrations of itraconazole. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions. Fluconazole: [see Pharmacokinetics (12.3)]
Anti-Gout Agents: Colchicine (in patients with renal or hepatic impairment) Colchicine (in patients with normal renal and hepatic function)	Contraindicated Use With Caution	Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. The dose of colchicine should be reduced when coadministered with clarithromycin in patients with normal renal and hepatic function [see Contraindications (4.4) and Warnings and Precautions (5.4)].
Antipsychotics: Pimozide Quetiapine	Contraindicated	Pimozide: [see Contraindications (4.2)] Quetiapine: Quetiapine is a substrate for CYP3A4, which is inhibited by clarithromycin. Coadministration with clarithromycin could result in increased quetiapine exposure and possible quetiapine related toxicities. There have been postmarketing reports of somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation during concomitant administration. Refer to quetiapine prescribing information for recommendations on dose reduction if coadministered with CYP3A4 inhibitors such as clarithromycin.
Antispasmodics: Tolterodine (patients deficient in CYP2D6 activity)	Use With Caution	Tolterodine: The primary route of metabolism for tolterodine is via CYP2D6. However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when coadministered with clarithromycin.
Antivirals: Atazanavir Saquinavir (in patients with decreased renal function) Ritonavir Etravirine Maraviroc Boceprevir (in patients with normal renal function) Didanosine Zidovudine	Use With Caution No Dose Adjustment	Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)]. Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction (see Saquinavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)]. Ritonavir, Etravirine: (see Ritonavir and Etravirine under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)]. Maraviroc: Clarithromycin may result in increases in maraviroc exposures by inhibition of CYP3A metabolism. See Selzentry^® prescribing information for dose recommendation when given with strong CYP3A inhibitors such as clarithromycin. Boceprevir: Both clarithromycin and boceprevir are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when coadministered. No dose adjustments are necessary for patients with normal renal function (see Victrelis^® prescribing information). Zidovudine: Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Administration of clarithromycin and zidovudine should be separated by at least two hours [see Pharmacokinetics (12.3)]. The impact of coadministration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated.
Calcium Channel Blockers: Verapamil Amlodipine Diltiazem Nifedipine	Use With Caution	Verapamil: Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, [see Warnings and Precautions (5.4)]. Amlodipine, Diltiazem: [see Warnings and Precautions (5.4)] Nifedipine: Nifedipine is a substrate for CYP3A. Clarithromycin and other macrolides are known to inhibit CYP3A. There is potential of CYP3A-mediated interaction between nifedipine and clarithromycin. Hypotension and peripheral edema were observed when clarithromycin was taken concomitantly with nifedipine [see Warnings and Precautions (5.4)].
Ergot Alkaloids: Ergotamine Dihydroergotamine	Contraindicated	Ergotamine, Dihydroergotamine: Postmarketing reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4.6)].
Gastroprokinetic Agents: Cisapride	Contraindicated	Cisapride: [see Contraindications (4.2)]
HMG-CoA Reductase Inhibitors: Lovastatin Simvastatin Atorvastatin Pravastatin Fluvastatin	Contraindicated Use With Caution No Dose Adjustment	Lovastatin, Simvastatin, Atorvastatin, Pravastatin, Fluvastatin: [see Contraindications (4.5) and Warnings and Precautions (5.4)]
Hypoglycemic Agents: Nateglinide Pioglitazone Repaglinide Rosiglitazone Insulin	Use With Caution	Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone: [see Warnings and Precautions (5.4) and Adverse Reactions (6.2)] Insulin: [see Warnings and Precautions (5.4) and Adverse Reactions (6.2)]
Immunosuppressants: Cyclosporine Tacrolimus	Use With Caution	Cyclosporine: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine. Tacrolimus: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with tacrolimus.
Phosphodiesterase inhibitors: Sildenafil Tadalafil Vardenafil	Use With Caution	Sildenafil, Tadalafil, Vardenafil: Each of these phosphodiesterase inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant administration of clarithromycin. Coadministration of clarithromycin with sildenafil, tadalafil, or vardenafil will result in increased exposure of these phosphodiesterase inhibitors. Coadministration of these phosphodiesterase inhibitors with clarithromycin is not recommended. Increased systemic exposure of these drugs may occur with clarithromycin; reduction of dosage for phosphodiesterase inhibitors should be considered (see their respective prescribing information).
Proton Pump Inhibitors: Omeprazole	No Dose Adjustment	Omeprazole: The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when coadministered with clarithromycin as a result of increased omeprazole exposures [see Pharmacokinetics (12.3)] (see also Omeprazole under “Drugs That Affect Clarithromycin” in the table below).
Xanthine Derivatives: Theophylline	Use With Caution	Theophylline: Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations [see Pharmacokinetics (12.3)]. Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range.
Triazolobenzodiazepines and Other Related Benzodiazepines: Midazolam Alprazolam Triazolam Temazepam Nitrazepam Lorazepam	Use With Caution No Dose Adjustment	Midazolam: When oral midazolam is coadministered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated [see Warnings and Precautions (5.4) and Pharmacokinetics (12.3)]. Triazolam, Alprazolam: Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is coadministered with clarithromycin. There have been postmarketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested. In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines. Temazepam, Nitrazepam, Lorazepam: For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.
Cytochrome P450 Inducers: Rifabutin	Use With Caution	Rifabutin: Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis (see Rifabutin under “Drugs That Affect Clarithromycin” in the table below).
Other Drugs Metabolized by CYP3A: Alfentanil Bromocriptine Cilostazol Methylprednisole Vinblastine Phenobarbital St. John’s Wort	Use With Caution	There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort.
Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A: Hexobarbital Phenytoin Valproate	Use With Caution	There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.
Drugs that Affect Clarithromycin
Drug(s) that Affect the Pharmacokinetics of Clarithromycin	Recommendation	Comments
Antifungals: Itraconazole	Use With Caution	Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions (see also Itraconazole under “Drugs That Are Affected By Clarithromycin” in the table above).
Antivirals: Atazanavir Ritonavir (in patients with decreased renal function) Saquinavir (in patients with decreased renal function) Etravirine Saquinavir (in patients with normal renal function) Ritonavir (in patients with normal renal function)	Use With Caution No Dose Adjustments	Atazanavir: When clarithromycin is coadministered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology (12.3)]. Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is coadministered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex. Doses of clarithromycin greater than 1000 mg per day should not be coadministered with protease inhibitors. Ritonavir: Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is coadministered with ritonavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium [see Pharmacokinetics (12.3)]. Doses of clarithromycin greater than 1000 mg per day should not be coadministered with protease inhibitors. Saquinavir: When saquinavir is coadministered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (refer to ritonavir above) [see Pharmacokinetics (12.3)]. Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.
Proton Pump Inhibitors: Omeprazole	Use With Caution	Omeprazole: Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole [see Pharmacokinetics (12.3)].
Miscellaneous Cytochrome P450 Inducers: Efavirenz Nevirapine Rifampicin Rifabutin Rifapentine	Use With Caution	Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are Affected By Clarithromycin” in the table above).

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents	Carefully monitor blood glucose ( 5.12, 7.3)

Table name:

Interacting DrugInteracting Drug	InteractionInteraction
Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products.
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents	Carefully monitor blood glucose ( 5.11, 7.3)

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
albuterol, systemic and inhaled	felodipinefinasteride	nizatidinenorfloxacin
amoxicillin	hydrocortisone	ofloxacin
ampicillin, with or without sulbactam	isofluraneisoniazid	omeprazoleprednisone, prednisolone
atenolol	isradipine	ranitidine
azithromycin	influenza vaccine	rifabutin
caffeine, dietary ingestion	ketoconazolelomefloxacin	roxithromycinsorbitol
cefaclor	mebendazole	(purgative doses do not
co-trimoxazole (trimethoprim and sulfamethoxazole)	medroxyprogesteronemethylprednisolone	inhibit theophylline absorption)
diltiazem	metronidazole	sucralfate
dirithromycin	metoprolol	terbutaline, systemic
enflurane	nadolol	terfenadine
famotidine	nifedipine	tetracycline
		tocainide
*Refer to PRECAUTIONS, Drug Interactions for information regarding table.

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Table 2: Drug Interactions: Pharmacokinetic Parameters for Indinavir in the Presence of the Coadministered Drug (See PRECAUTIONS, Table 9 for Recommended Alterations in Dose or Regimen)
Coadministered drug	Dose of Coadministered drug (mg)	Dose of CRIXIVAN (mg)	n	Ratio (with/without coadministered drug) of Indinavir Pharmacokinetic Parameters (90% CI); No Effect = 1.00
				C_max	AUC	C_min
All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
Cimetidine	600 twice daily, 6 days	400 single dose	12	1.07 (0.77, 1.49)	0.98 (0.81, 1.19)	0.82 (0.69, 0.99)
Clarithromycin	500 q12h, 7 days	800 three times daily, 7 days	10	1.08 (0.85, 1.38)	1.19 (1.00, 1.42)	1.57 (1.16, 2.12)
Delavirdine	400 three times daily	400 three times daily, 7 days	28	0.64Relative to indinavir 800 mg three times daily alone. (0.48, 0.86)	No significant change	2.18 (1.16, 4.12)
Delavirdine	400 three times daily	600 three times daily, 7 days	28	No significant change	1.53 (1.07, 2.20)	3.98 (2.04, 7.78)
EfavirenzStudy conducted in HIV-positive subjects.	600 once daily, 10 days	1000 three times daily, 10 days	20
		After morning dose		No significant change	0.67 (0.61, 0.74)	0.61 (0.49, 0.76)
		After afternoon dose		No significant change	0.63 (0.54, 0.74)	0.48 (0.43, 0.53)
		After evening dose		0.71 (0.57, 0.89)	0.54 (0.46, 0.63)	0.43 (0.37, 0.50)
Fluconazole	400 once daily, 8 days	1000 three times daily, 7 days	11	0.87 (0.72, 1.05)	0.76 (0.59, 0.98)	0.90 (0.72, 1.12)
Grapefruit Juice	8 oz.	400 single dose	10	0.65 (0.53, 0.79)	0.73 (0.60, 0.87)	0.90 (0.71, 1.15)
Isoniazid	300 once daily in the morning, 8 days	800 three times daily, 7 days	11	0.95 (0.88, 1.03)	0.99 (0.87, 1.13)	0.89 (0.75, 1.06)
Itraconazole	200 twice daily, 7 days	600 three times daily, 7 days	12	0.78 (0.69, 0.88)	0.99 (0.91, 1.06)	1.49 (1.28, 1.74)
Ketoconazole	400 once daily, 7 days	600 three times daily, 7 days	12	0.69 (0.61, 0.78)	0.80 (0.74, 0.87)	1.29 (1.11, 1.51)
	400 once daily, 7 days	400 three times daily, 7 days	12	0.42 (0.37, 0.47)	0.44 (0.41, 0.48)	0.73 (0.62, 0.85)
Methadone	20-60 once daily in the morning, 8 days	800 three times daily, 8 days	10	See text below for discussion of interaction.
Quinidine	200 single dose	400 single dose	10	0.96 (0.79, 1.18)	1.07 (0.89, 1.28)	0.93 (0.73, 1.19)
Rifabutin	150 once daily in the morning, 10 days	800 three times daily, 10 days	14	0.80 (0.72, 0.89)	0.68 (0.60, 0.76)	0.60 (0.51, 0.72)
Rifabutin	300 once daily in the morning, 10 days	800 three times daily, 10 days	10	0.75 (0.61, 0.91)	0.66 (0.56, 0.77)	0.61 (0.50, 0.75)
Rifampin	600 once daily in the morning, 8 days	800 three times daily, 7 days	12	0.13 (0.08, 0.22)	0.08 (0.06, 0.11)	Not Done
Ritonavir	100 twice daily, 14 days	800 twice daily, 14 days	10, 16Comparison to historical data on 16 subjects receiving indinavir alone.	See text below for discussion of interaction.
Ritonavir	200 twice daily, 14 days	800 twice daily,14 days	9, 16	See text below for discussion of interaction.
Sildenafil	25 single dose	800 three times daily	6	See text below for discussion of interaction.
St. John's wort (Hypericum perforatum, standardized to 0.3 % hypericin)	300 three times daily with meals, 14 days	800 three times daily	8	Not Available	0.46 (0.34, 0.58)95% CI.	0.19 (0.06, 0.33)
Stavudine (d4T)	40 twice daily, 7 days	800 three times daily, 7 days	11	0.95 (0.80, 1.11)	0.95 (0.80, 1.12)	1.13 (0.83, 1.53)
Trimethoprim/ Sulfamethoxazole	800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days	400 four times daily, 7 days	12	1.12 (0.87, 1.46)	0.98 (0.81, 1.18)	0.83 (0.72, 0.95)
Zidovudine	200 three times daily, 7 days	1000 three times daily, 7 days	12	1.06 (0.91, 1.25)	1.05 (0.86, 1.28)	1.02 (0.77, 1.35)
Zidovudine/ Lamivudine (3TC)	200/150 three times daily, 7 days	800 three times daily, 7 days	6, 9Parallel group design; n for indinavir + coadministered drug, n for indinavir alone.	1.05 (0.83, 1.33)	1.04 (0.67, 1.61)	0.98 (0.56, 1.73)

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Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference)		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	Cmax	Risperidone Dose Recommendation
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP34A inhibitors (e.g. itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 5. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug Name	Effect on Concentration of Ritonavir or Concomitant Drug	Clinical Comment
HIV-Antiviral Agents
HIV-1 Protease Inhibitor: atazanavir darunavir fosamprenavir	↑ amprenavir ↑ atazanavir ↑ darunavir	See the complete prescribing information for fosamprenavir, atazanavir, darunavir for details on co-administration with ritonavir.
HIV-1 Protease Inhibitor: indinavir	↑ indinavir	Appropriate doses for this combination, with respect to efficacy and safety, have not been established.
HIV-1 Protease Inhibitor: saquinavir	↑ saquinavir	See the complete prescribing information for saquinavir for details on co-administration of saquinavir and ritonavir. Saquinavir/ritonavir in combination with rifampin is not recommended due to the risk of severe hepatotoxicity (presenting as increased hepatic transaminases) if the three drugs are given together.
HIV-1 Protease Inhibitor: tipranavir	↑ tipranavir	See the complete prescribing information for tipranavir for details on co-administration of tipranavir and ritonavir.
Non-Nucleoside Reverse Transcriptase Inhibitor: delavirdine	↑ ritonavir	Appropriate doses of this combination with respect to safety and efficacy have not been established.
HIV-1 CCR5 – antagonist: maraviroc	↑ maraviroc	See the complete prescribing information for maraviroc for details on co-administration of maraviroc and ritonavir-containing protease inhibitors.
Integrase Inhibitor: raltegravir	↓ raltegravir	The effects of ritonavir on raltegravir with ritonavir dosage regimens greater than 100 mg twice daily have not been evaluated, however raltegravir concentrations may be decreased with ritonavir coadministration.
Other Agents
Analgesics, Narcotic: tramadol, propoxyphene, methadone, fentanyl	↑ analgesics ↓ methadone ↑ fentanyl	A dose decrease may be needed for these drugs when co-administered with ritonavir. Dosage increase of methadone may be considered. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with NORVIR.
Anesthetic: meperidine	↓ meperidine/ ↑ normeperidine (metabolite)	Dosage increase and long-term use of meperidine with ritonavir are not recommended due to the increased concentrations of the metabolite normeperidine which has both analgesic activity and CNS stimulant activity (e.g., seizures).
Antialcoholics: disulfiram/ metronidazole		Ritonavir formulations contain ethanol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Antiarrhythmics: disopyramide, lidocaine, mexiletine	↑ antiarrhythmics	For contraindicated antiarrhythmics [see Contraindications (4)]. Caution is warranted and therapeutic concentration monitoring is recommended for antiarrhythmics when co-administered with ritonavir, if available.
Anticancer Agents: dasatinib, nilotinib, venetoclax, vincristine, vinblastine	↑ anticancer agents	For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when ritonavir is administered concurrently with vincristine or vinblastine. Clinicians should be aware that if the ritonavir containing regimen is withheld for a prolonged period, consideration should be given to altering the regimen to not include a CYP3A or P-gp inhibitor in order to control HIV-1 viral load. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as NORVIR. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions. Coadministration of venetoclax and NORVIR may increase the risk of tumor lysis syndrome. Refer to the venetoclax prescribing information for dosing instructions.
Anticoagulant: warfarin	↑↓ warfarin	Initial frequent monitoring of the INR during ritonavir and warfarin co-administration is recommended.
Anticoagulant: rivaroxaban	↑ rivaroxaban	Avoid concomitant use of rivaroxaban and ritonavir. Co-administration of ritonavir and rivaroxaban may lead to risk of increased bleeding.
Anticonvulsants: carbamazepine, clonazepam, ethosuximide	↑ anticonvulsants	A dose decrease may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available.
Anticonvulsants: divalproex, lamotrigine, phenytoin	↓ anticonvulsants	A dose increase may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available.
Antidepressants: nefazodone, selective serotonin reuptake inhibitors (SSRIs): e.g. fluoxetine, paroxetine, tricyclics: e.g. amitriptyline, nortriptyline	↑ antidepressants	A dose decrease may be needed for these drugs when co-administered with ritonavir.
Antidepressant: bupropion	↓ bupropion ↓ active metabolite, hydroxybupropion	Patients receiving ritonavir and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant: desipramine	↑ desipramine	Dosage reduction and concentration monitoring of desipramine is recommended.
Antidepressant: trazodone	↑ trazodone	Adverse events of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and NORVIR. A lower dose of trazodone should be considered.
Antiemetic: dronabinol	↑ dronabinol	A dose decrease of dronabinol may be needed when co-administered with ritonavir.
Antifungals: ketoconazole itraconazole voriconazole	↑ ketoconazole ↑ itraconazole ↓ voriconazole	For contraindicated antifungals, [see Contraindications (4)]. High doses of ketoconazole or itraconazole (greater than 200 mg per day) are not recommended. Co-administration of voriconazole and ritonavir doses of 400 mg every 12 hours or greater is contraindicated [see Contraindications (4)]. Co-administration of voriconazole and ritonavir 100 mg should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.
Anti-gout: colchicine	↑ colchicine	Concomitant administration with colchicine is contraindicated in patients with renal and/or hepatic impairment [see Contraindications (4)]. For patients with normal renal or hepatic function: Treatment of gout flares-co-administration of colchicine in patients on ritonavir: 0.6 mg (one tablet) for one dose, followed by 0.3 mg (half tablet) one hour later. Dose to be repeated no earlier than three days. Prophylaxis of gout flares-co-administration of colchicine in patients on ritonavir: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on ritonavir: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Anti-infective: clarithromycin	↑ clarithromycin	For patients with renal impairment, adjust clarithromycin dose as follows: For patients with CL_CR 30 to 60 mL per min the dose of clarithromycin should be reduced by 50%. For patients with CL_CR less than 30 mL per min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary.
Antimycobacterial: bedaquiline	↑ bedaquiline	Bedaquiline should only be used with ritonavir if the benefit of co-administration outweighs the risk.
Antimycobacterial: rifabutin	↑ rifabutin and rifabutin metabolite	Dosage reduction of rifabutin by at least three-quarters of the usual dose of 300 mg per day is recommended (e.g., 150 mg every other day or three times a week). Further dosage reduction may be necessary.
Antimycobacterial: rifampin	↓ ritonavir	May lead to loss of virologic response. Alternate antimycobacterial agents such as rifabutin should be considered.
Antiparasitic: atovaquone	↓ atovaquone	Clinical significance is unknown; however, increase in atovaquone dose may be needed.
Antiparasitic: quinine	↑ quinine	A dose decrease of quinine may be needed when co-administered with ritonavir.
Antipsychotics: perphenazine, risperidone, thioridazine	↑ antipsychotics	For contraindicated antipsychotics, [see Contraindications (4)]. A dose decrease may be needed for these drugs when co-administered with ritonavir.
Antipsychotics: quetiapine	↑ quetiapine	Initiation of NORVIR in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking NORVIR: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
β-Blockers: metoprolol, timolol	↑ beta-blockers	Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with ritonavir.
Bronchodilator: theophylline	↓ theophylline	Increased dosage of theophylline may be required; therapeutic monitoring should be considered.
Calcium channel blockers: diltiazem, nifedipine, verapamil	↑ calcium channel blockers	Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with ritonavir.
Digoxin	↑ digoxin	Concomitant administration of ritonavir with digoxin may increase digoxin levels. Caution should be exercised when co-administering ritonavir with digoxin, with appropriate monitoring of serum digoxin levels.
Endothelin receptor antagonists: bosentan	↑ bosentan	Co-administration of bosentan in patients on ritonavir: In patients who have been receiving ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Co-administration of ritonavir in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of ritonavir. After at least 10 days following the initiation of ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Hepatitis C direct acting antiviral: simeprevir	↑simeprevir	It is not recommended to co-administer ritonavir with simeprevir.
HMG-CoA Reductase Inhibitor: atorvastatin rosuvastatin	↑ atorvastatin ↑ rosuvastatin	For contraindicated HMG-CoA reductase inhibitors, [see Contraindications (4)]. Titrate atorvastatin and rosuvastatin dose carefully and use the lowest necessary dose. If NORVIR is used with another protease inhibitor, see the complete prescribing information for the concomitant protease inhibitor for details on co-administration with atorvastatin and rosuvastatin.
Immunosuppressants: cyclosporine, tacrolimus, sirolimus (rapamycin)	↑ immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with ritonavir.
Systemic/Inhaled/ Nasal/Ophthalmic Corticosteroids: e.g., betamethasone budesonide ciclesonide dexamethasone fluticasone methylprednisolone mometasone prednisone triamcinolone	↑ glucocorticoids	Coadministration with corticosteroids whose exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression. Alternative corticosteroids including beclomethasone and prednisolone (whose PK and/or PD are less affected by strong CYP3A inhibitors relative to other studied steroids) should be considered, particularly for long-term use.
Long-acting beta-adrenoceptor agonist: salmeterol	↑ salmeterol	Concurrent administration of salmeterol and ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Oral Contraceptives or Patch Contraceptives: ethinyl estradiol	↓ ethinyl estradiol	Alternate methods of contraception should be considered.
PDE5 Inhibitors: avanafil sildenafil, tadalafil, vardenafil	↑ avanafil ↑ sildenafil ↑ tadalafil ↑ vardenafil	For contraindicated PDE5 inhibitors, [see Contraindications (4)]. Do not use ritonavir with avanafil because a safe and effective avanafil dosage regimen has not been established. Particular caution should be used when prescribing sildenafil, tadalafil or vardenafil in patients receiving ritonavir. Coadministration of ritonavir with these drugs may result in an increase in PDE5 inhibitor associated adverse events, including hypotension, syncope, visual changes, and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio^®) is contraindicated [see Contraindications (4)]. The following dose adjustments are recommended for use of tadalafil (Adcirca^®) with ritonavir: Co-administration of ADCIRCA in patients on ritonavir: In patients receiving ritonavir for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Co-administration of ritonavir in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of ritonavir. Stop ADCIRCA at least 24 hours prior to starting ritonavir. After at least one week following the initiation of ritonavir, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for the treatment of erectile dysfunction: It is recommended not to exceed the following doses: Sildenafil: 25 mg every 48 hours Tadalafil: 10 mg every 72 hours Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events.
Sedative/hypnotics: buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem	↑ sedative/hypnotics	A dose decrease may be needed for these drugs when co-administered with ritonavir.
Sedative/hypnotics: Parenteral midazolam	↑ midazolam	For contraindicated sedative/hypnotics, [see Contraindications (4)]. Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.
Stimulant: methamphetamine	↑ methamphetamine	Use with caution. A dose decrease of methamphetamine may be needed when co-administered with ritonavir.

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone.

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DRUG	DESCRIPTION OF INTERACTION
Sulfonylureas	Hypoglycemia potentiated.
Methotrexate	Decreases tubular reabsorption; clinical toxicityfrom methotrexate can result.
Oral Anticoagulants	Increased bleeding.

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Digoxin concentrations increased greater than 50%
	Digoxin Serum Concentration Increase	Digoxin AUC Increase	Recommendations
Amiodarone	70%	NA	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30 to 50% or by modifying the dosing frequency and continue monitoring.
Captopril	58%	39%
Clarithromycin	NA	70%
Dronedarone	NA	150%
Gentamicin	129 to 212%	NA
Erythromycin	100%	NA
Itraconazole	80%	NA
Lapatinib	NA	180%
Propafenone	NA	60 to 270%
Quinidine	100%	NA
Ranolazine	50%	NA
Ritonavir	NA	86%
Telaprevir	50%	85%
Tetracycline	100%	NA
Verapamil	50 to 75%	NA
Digoxin concentrations increased less than 5 0 %
Atorvastatin	22%	15%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15 to 30% or by modifying the dosing frequency and continue monitoring.
Carvedilol	16%	14%
Conivaptan	33%	43%
Diltiazem	20%	NA
Indomethacin	40%	NA
Nefazodone	27%	15%
Nifedipine	45%	NA
Propantheline	24%	24%
Quinine	NA	33%
Rabeprazole	29%	19%
Saquinavir	27%	49%
Spironolactone	25%	NA
Telmisartan	20 to 49%	NA
Ticagrelor	31%	28%
Tolvaptan	30%	20 %
Trimethoprim	22 to 28%	NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate and sulfasalazine			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20 to 40 % as necessary.

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Table 1: Drugs that may have their plasma concentrations increased by itraconazole
Drug Class	Contraindicated	Not Recommended	Use with Caution	Comments
	Under no circumstances is the drug to be coadministered with itraconazole, and up to two weeks after discontinuation of treatment with itraconazole.	It is recommended that the use of the drug be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If coadministration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of the interacting drug is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured. The label of the coadministered drug should be consulted for information on dose adjustment and adverse effects.	Careful monitoring is recommended when the drug is coadministered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of the interacting drug, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured. The label of the coadministered drug should be consulted for information on dose adjustment and adverse effects.
Alpha Blockers		tamsulosin
Analgesics	methadone		alfentanil, buprenorphine IV and sublingual, fentanyl, oxycodone, sufentanil	Methadone: The potential increase in plasma concentrations of methadone when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation and torsade de pointes. Fentanyl: The potential increase in plasma concentrations of fentanyl when coadministered with itraconazole may increase the risk of potentially fatal respiratory depression. Sufentanil: No human pharmacokinetic data of an interaction with itraconazole are available. In vitro data suggest that sufentanil is metabolized by CYP3A4 and so potentially increased sufentanil plasma concentrations would be expected when coadministered with itraconazole.
Antiarrhythmics	disopyramide, dofetilide, dronedarone, quinidine		digoxin	Disopyramide, dofetilide, dronedarone, quinidine: The potential increase in plasma concentrations of these drugs when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation.
Antibacterials	telithromycin, in subjects with severe renal impairment or severe hepatic impairment	rifabutin	telithromycin	Telithromycin: The potential increase in plasma concentrations of telithromycin in subjects with severe renal impairment or severe hepatic impairment, when coadministered with itraconazole may increase the risk of serious cardiovascular events including QT prolongation and torsade de pointes. Rifabutin: See also under ‘Drugs that may decrease itraconazole plasma concentrations’.
Anticoagulants and Antiplatelet Drugs	ticagrelor	apixaban, rivaroxaban	coumarins, cilostazol, dabigatran	Ticagrelor: The potential Increase in plasma concentrations of ticagrelor may increase the risk of bleeding. Coumarins: Itraconazole may enhance the anticoagulant effect of coumarin-like drugs, such as warfarin.
Anticonvulsants		carbamazepine		Carbamazepine: In vivo studies have demonstrated an increase in plasma carbamazepine concentrations in subjects concomitantly receiving ketoconazole. Although there are no data regarding the effect of itraconazole on carbamazepine metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of itraconazole and carbamazepine may inhibit the metabolism of carbamazepine. See also under ‘Drugs that may decrease itraconazole plasma concentrations’.
Antidiabetics			repaglinide, saxagliptin
Antihelmintics and Antiprotozoals			praziquantel
Antimigraine Drugs	ergot alkaloids, such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine)		eletriptan	Ergot Alkaloids: The potential increase in plasma concentrations of ergot alkaloids when coadministered with itraconazole may increase the risk of ergotism, ie. a risk for vasospasm potentially leading to cerebral ischemia and/or ischemia of the extremities.
Antineoplastics	irinotecan	axitinib, dabrafenib, dasatinib, ibrutinib, nilotinib, sunitinib	bortezomib, busulphan, docetaxel, erlotinib, imatinib, ixabepilone, lapatinib, ponatinib, trimetrexate, vinca alkaloids	Irinotecan: The potential increase in plasma concentrations of irinotecan when coadministered with itraconazole may increase the risk of potentially fatal adverse events.
Antipsychotics, Anxiolytics and Hypnotics	lurasidone, oral midazolam, pimozide, triazolam		alprazolam, aripiprazole, buspirone, diazepam, haloperidol, midazolam IV, perospirone, quetiapine, ramelteon, risperidone	Midazolam, triazolam: Coadministration of itraconazole and oral midazolam, or triazolam may cause several-fold increases in Plasma concentrations of these drugs. This may potentiate and prolong hypnotic and sedative effects, especially with repeated dosing or chronic administration of these agents. Pimozide: The potential increase in plasma concentrations of pimozide when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation and torsade de pointes.
Antivirals		simeprevir	maraviroc, indinavir, ritonavir, saquinavir	Indinavir, ritonavir: See also under ‘Drugs that may increase itraconazole plasma concentrations’.
Beta Blockers			nadolol
Calcium Channel Blockers	felodipine, nisoldipine		other dihydropyridines, verapamil	Calcium channel blockers can have a negative inotropic effect which may be additive to those of itraconazole. The potential increase in plasma concentrations of calcium channel blockers when co-administered with itraconazole may increase the risk of congestive heart failure. Dihydropyridines: Concomitant administration of itraconazole may cause several-fold increases inplasma concentrations of dihydropyridines. Edema has been reported in patients concomitantly receiving itraconazole and dihydropyridine calcium channel blockers.
Cardiovascular Drugs, Miscellaneous	ranolazine	aliskiren, sildenafil, for the treatment of pulmonary hypertension	bosentan, riociguat	Ranolazine: The potential increase in plasma concentrations of ranolazine when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation.
Diuretics	eplerenone			Eplerenone: The potential increase in plasma concentrations of eplerenone when coadministered with itraconazole may increase the risk of hyperkalemia and hypotension.
Gastrointestinal Drugs	cisapride		aprepitant	Cisapride: The potential increase in plasma concentrations of cisapride when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation.
Immunosuppressants		everolimus, temsirolimus	budesonide, ciclesonide, cyclosporine, dexamethasone, fluticasone, methylprednisolone, rapamycin (also known as sirolimus), tacrolimus
Lipid Regulating Drugs	lovastatin, simvastatin		atorvastatin	The potential increase in plasma concentrations of atorvastatin, lovastatin, and simvastatin when coadministered with itraconazole may increase the risk of skeletal muscle toxicity, including rhabdomyolysis.
Respiratory Drugs		salmeterol
Urological Drugs	fesoterodine, in subjects with moderate to severe renal impairment, or moderate to severe hepatic impairment, solifenacin, in subjects with severe renal impairment or moderate to severe hepatic impairment	darifenacin, vardenafil	fesoterodine. oxybutynin, sildenafil, for the treatment of erectile dysfunction, solifenacin, tadalafil, tolterodine	Fesoterodine: The potential increase in plasma concentrations of the fesoterodine active metabolite may be greater in subjects with moderate to severe renal impairment, or moderate to severe hepatic impairment, which may lead to an increased risk of adverse reactions. Solifenacin: The potential increase in plasma concentrations of solifenacin in subjects with severe renal impairment or moderate to severe hepatic impairment, when coadministered with itraconazole may increase the risk of serious cardiovascular events including QT prolongation.
Other	colchicine, in subjects with renal or hepatic impairment	colchicine, conivaptan, tolvaptan	cinacalcet	Colchicine: The potential increase in plasma concentrations of colchicine when coadministered with itraconazole may increase the risk of potentially fatal adverse events. Conivaptan and Tolvaptan: A safe and effective dose of either conivaptan or tolvaptan has not been established when coadministered with itraconazole.

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin	Monitor phenytoin level (7)
Methotrexate	Monitor for methotrexate toxicity (7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation- containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)

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Drugs That Interfere with Hemostasis
Clinical Impact:	• Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	• During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

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Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
* Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing.
	20 mg/day	4 mg/day	1.6	-	Do not exceed 8 mg/day
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed

Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Figure 7: Mean Standing Systolic Blood Pressure Change from Baseline

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine	Do not exceed 10 mg atorvastatin daily
Clarithromycin, itraconazole, HIV protease inhibitors (ritonavir plus saquinavir or lopinavir plus ritonavir)	Caution when exceeding doses > 20 mg atorvastatin daily. The lowest dose necessary should be used.

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Interacting DrugInteracting Drug	InteractionInteraction
Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products.
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents	Carefully monitor blood glucose ( 5.11, 7.3)

Table name: Gemfibrozil ClopidogrelCyclosporineCYP2C8 and CYP3A4 InhibitorsCYP2C8 and CYP3A4 InducersDrugs That May Increase the Risk of HypoglycemiaDrugs That May Decrease the Blood Glucose Lowering Effect of PRANDINDrugs That May Blunt Signs and Symptoms of Hypoglycemia



Clinical Impact:	Gemfibrozil significantly increased repaglinide exposures by 8.1 fold [see Clinical Pharmacology (12.3)]
Intervention:	Do not administer PRANDIN to patients receiving gemfibrozil [see Contraindications (4)].

Clinical Impact:	Clopidogrel increased repaglinide exposures by 3.9-5.1 fold [see Clinical Pharmacology (12.3)]
Intervention:	Avoid concomitant use of PRANDIN with clopidogrel. If concomitant use can not be avoided, initiate PRANDIN at 0.5 mg before each meal and do not exceed a total daily dose of 4 mg [see DOSAGE AND ADMINISTRATION (2.3)]. Increased frequency of glucose monitoring may be required during concomitant use.

Clinical Impact:	Cyclosporine increased low dose repaglinide exposures by 2.5 fold [see Clinical Pharmacology (12.3)]
Intervention:	Daily maximum PRANDIN dose should be limited to 6 mg, and increased frequency of glucose monitoring may be required when PRANDIN is co-administered with cyclosporine.

Intervention:	PRANDIN dose reductions and increased frequency of glucose monitoring may be required when co-administered.
Examples:	Drugs that are known to inhibit CYP3A4 include antifungal agents (ketoconazole, itraconazole) and antibacterial agents (clarithromycin, erythromycin). Drugs that are known to inhibit CYP2C8 include trimethoprim, gemfibrozil, montelukast, deferasirox, and clopidiogrel.

Intervention:	PRANDIN dose increases and increased frequency of glucose monitoring may be required when co-administered.
Examples:	Drugs that induce the CYP3A4 and/or 2C8 enzyme systems include rifampin, barbiturates, and carbamezapine

Intervention:	PRANDIN dose reductions and increased frequency of glucose monitoring may be required when co-administered.
Examples:	Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, nonsteroidal anti-inflammatory agents (NSAIDs), pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics

Intervention:	PRANDIN dose increases and increased frequency of glucose monitoring may be required when co-administered.
Examples:	Atypical antipsychotics (e.g., olanzapine and clozapine), calcium channel antagonists, corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones.

Intervention:	Increased frequency of glucose monitoring may be required when PRANDIN is co-administered with these drugs.
Examples:	beta-blockers, clonidine, guanethidine, and reserpine

Table 2. Effects of Other Drugs on MOVANTIK
Concomitant Agent	Mechanism of Action
CYP3A4 Inhibitors
















Other Drug Interactions

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Drugs That May Potentiate Renal Dysfunction
Antibiotics	Antineoplastics	Anti-inflammatory Drugs	Gastrointestinal Agents
ciprofloxacin gentamicin tobramycin vancomycin trimethoprim with sulfamethoxazole	melphalan	azapropazon colchicine diclofenac naproxen sulindac	cimetidine ranitidine
	Antifungals		cimetidine ranitidine
	amphotericin B ketoconazole		Immunosuppressives
			tacrolimus
			Other Drugs
			fibric acid derivatives (e.g., bezafibrate, fenofibrate) methotrexate

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Clinically significant drug interactions with BUPRENEX.
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see WARNINGS].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids, alcohol.
Inhibitors of CYP3A4
Clinical Impact:	The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of BUPRENEX is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease [see CLINICAL PHARMACOLOGY: Pharmacokinetics], potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to buprenorphine.
Intervention:	If concomitant use is necessary, consider dosage reduction of BUPRENEX until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the BUPRENEX dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples:	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact:	The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine [see CLINICAL PHARMACOLOGY: Pharmacokinetics] , potentially resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase [see CLINICAL PHARMACOLOGY: Pharmacokinetics] , which could increase or prolong both therapeutic effects and adverse reactions and may cause serious respiratory depression.
Intervention:	If concomitant use is necessary, consider increasing the BUPRENEX dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider BUPRENEX dosage reduction and monitor for signs of respiratory depression.
Examples:	Rifampin, carbamazepine, phenytoin
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue BUPRENEX if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome opioid toxicity (e.g., respiratory depression, coma).
Intervention:	The use of BUPRENEX is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of BUPRENEX and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine
Muscle Relaxants
Clinical Impact:	Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients receiving muscle relaxants and BUPRENEX for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of BUPRENEX and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when BUPRENEX is used concomitantly with anticholinergic drugs.
Antiretrovirals: Nucleoside reverse transcriptase inhibitors (NRTIs)
Clinical Impact:	Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected.
Intervention:	None
Antiretrovirals: Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Clinical Impact:	Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine, and etravirine are known CYP3A inducers, whereas delaviridine is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects.
Intervention:	Patients who are on chronic BUPRENEX treatment should have their dose monitored if NNRTIs are added to their treatment regimen.
Examples:	efavirenz, nevirapine, etravirine, delavirdine
Antiretrovirals: Protease inhibitors (PIs)
Clinical Impact:	Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity (atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine, and patients in one study reported increased sedation. Symptoms of opioid excess have been found in post-marketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly.
Intervention:	Monitor patients taking BUPRENEX and atazanavir with and without ritonavir, and dose reduction of BUPRENEX may be warranted.
Examples:	atazanavir, ritonavir

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CYP2C19 or CYP3A4 Inducers
Clinical Impact:	Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention:	St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions (5.9)]. Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:	Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
Intervention:	Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole.

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Calcium Channel BIockers	Antifungals	Antibiotics	Glucocorticoids	Other Drugs
diltiazem nicardipine verapamil	fluconazole itraconazole ketoconazole voriconazole	azithromycin clarithromycin erythromycin quinupristin/dalfopristin	methylprednisolone	allopurinol amiodarone bromocriptine colchicine danazol imatinib metoclopramide nefazodone oral contraceptives

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 4: Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
Drug Name	Effect on Concentration of Nevirapine or Concomitant Drug	Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/RitonavirThe interaction between immediate-release nevirapine and the drug was evaluated in a clinical study. The results of drug interaction studies with immediate-release nevirapine are expected to also apply to nevirapine extended-release tablets.	↓ Atazanavir ↑ Nevirapine	Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir	↓ Amprenavir ↑ Nevirapine	Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir	↓ Amprenavir ↑ Nevirapine	No dosing adjustments are required when nevirapine is co-administered with 700 mg/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir	↓ Indinavir	The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir	↓ Lopinavir	Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500 mg/125 mg tablets twice daily or 533 mg/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra^® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir	↓ Nelfinavir M8 Metabolite ↓ Nelfinavir C_min	The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/Ritonavir	The interaction between nevirapine and saquinavir/ritonavir has not been evaluated	The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz	↓ Efavirenz	The appropriate doses of these combinations with respect to safety and efficacy have not been established.
Delavirdine Etravirine Rilpivirine		Plasma concentrations may be altered. Nevirapine should not be co-administered with another NNRTI as this combination has not been shown to be beneficial.
Hepatitis C Antiviral Agents
Boceprevir	Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine.	Nevirapine and boceprevir should not be co-administered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy.
Telaprevir	Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir.	Nevirapine and telaprevir should not be co-administered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events.
Other Agents
Analgesics: Methadone	↓ Methadone	Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics: Amiodarone, disopyramide, lidocaine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Antibiotics: Clarithromycin	↓ Clarithromycin ↑ 14-OH clarithromycin	Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Rifabutin	↑ Rifabutin	Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin	↓ Nevirapine	Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants: Carbamazepine, clonazepam, ethosuximide	Plasma concentrations of nevirapine and the anticonvulsant may be decreased.	Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals: Fluconazole	↑ Nevirapine	Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Ketoconazole	↓ Ketoconazole	Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Itraconazole	↓ Itraconazole	Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics: Warfarin	Plasma concentrations may be increased.	Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers: Diltiazem, nifedipine, verapamil	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Cancer chemotherapy: Cyclophosphamide	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Ergot alkaloids: Ergotamine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Motility agents: Cisapride	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Opiate agonists: Fentanyl	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Oral contraceptives: Ethinyl estradiol and Norethindrone	↓ Ethinyl estradiol ↓ Norethindrone	Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.

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Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)	VIAGRA 100 mg
Supine	7.9 (4.6, 11.1)
Standing	4.3 (-1.8,10.3)

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
↓= Decreased (induces lamotrigine gluronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ?= Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
	? CBZ epoxide	May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Factors	Dosage Adjustment of aripiprazole
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors	Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double usual dose over 1 to 2 weeks

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol,	famotidine	nizatidine
systemic and inhaled	felodipine	norfloxacin
amoxicillin	finasteride	ofloxacin
ampicillin,	hydrocortisone	omeprazole
with or without	isoflurane	prednisone, prednisolone
sulbactam	isoniazid	ranitidine
atenolol	isradipine	rifabutin
azithromycin	influenza vaccine	roxithromycin
caffeine,	ketoconazole	sorbitol
dietary ingestion	lomefloxacin	(purgative doses do not
cefaclor	mebendazole	inhibit theophylline
co-trimoxazole	medroxyprogesterone	absorption)
(trimethoprim and	methylprednisolone	sucralfate
sulfamethoxazole)	metronidazole	terbutaline, systemic
diltiazem	metoprolol	terfenadine
dirithromycin	nadolol	tetracycline
enflurane	nifedipine	tocainide

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Table 2 Clinically Significant Drug Interactions with Indomethacin
Drugs That Interfere with Hemostasis
Clinical Impact:	Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of indomethacin extended-release capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention:	Concomitant use of indomethacin extended-release capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Indomethacin extended-release capsules are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of indomethacin extended-release capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of indomethacin extended-release capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. It has been reported that the addition of triamterene to a maintenance schedule of indomethacin extended-release capsules resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin extended-release capsules and triamterene should not be administered together. Both indomethacin extended-release capsules and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin extended-release capsules and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently.
Intervention:	Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin extended-release capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact:	The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of indomethacin extended-release capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of indomethacin extended-release capsules and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of indomethacin extended-release capsules and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of indomethacin extended-release capsules and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of indomethacin extended-release capsules and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin [see Clinical Pharmacology (12.3)]. In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage.
Intervention:	The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of indomethacin extended-release capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of indomethacin extended-release capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Probenecid
Clinical Impact:	When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased.
Intervention:	During the concomitant use of indomethacin extended-release capsules and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments.

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Drugs That Interfere with Hemostasis
Clinical Impact:	• Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. · Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention:	• Concomitant use of naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. • Naproxen sodium tablets are not substitutes for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	• During concomitant use of naproxen sodium and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin
Intervention:	During concomitant use of naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	· During concomitant use of naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. · NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. · In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen sodium tablets are not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxen sodium tablet is not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen sodium tablets and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:	Patients simultaneously receiving naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

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Table 2: Clinically Significant Drug Interactions with Mefenamic Acid
Drugs That Interfere with Hemostasis
Clinical Impact :	• Mefenamic acid and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of mefenamic acid and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention :	Monitor patients with concomitant use of mefenamic acid with anticoagulants (e.g.,warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact :	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention :	Concomitant use of mefenamic acid and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Mefenamic acid is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors , Angiotensin Receptor Blockers , and Beta - Blockers
Clinical Impact :	• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention :	• During concomitant use of mefenamic acid and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of mefenamic acid and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact :	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention	During concomitant use of mefenamic acid with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact :	The concomitant use of mefenamic acid with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention :	During concomitant use of mefenamic acid and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact :	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention :	During concomitant use of mefenamic acid and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact :	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention :	During concomitant use of mefenamic acid and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact :	Concomitant use of mefenamic acid and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention :	During concomitant use of mefenamic acid and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact :	Concomitant use of mefenamic acid with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention :	The concomitant use of mefenamic acid with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact :	Concomitant use of mfenamic acid and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention :	During concomitant use of mefenamic acid and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacid
Clinical Impact :	In a single dose study (n= 6), ingestion of an antacid containing 1.7-gram of magnesium hydroxide with 500-mg of mefenamic acid increased the C_m _a _x and AUC of mefenamic acid by 125% and 36%, respectively.
Intervention :	Concomitant use of mefenamic acid and antacids is not generally recommended because of possible increased adverse events.

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Placebo-subtracted mean maximum decrease in systolic blood pressure (mm Hg)	VIAGRA 25 mg
Supine	7.4 (-0.9, 15.7)
Standing	6.0 (-0.8, 12.8)

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitors (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine,danazol	Do not exceed 10 mg simvastatindaily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem	Do not exceed 40 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Interacting DrugInteracting Drug	InteractionInteraction
Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products ( 2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents	Carefully monitor blood glucose ( 5.12, 7.3)

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C Protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Interacting Agents	Prescribing Recommendation
Strong CYP3A4 inhibitors (e.g,. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir nefazodone, cobicistatcontaining products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily*
Grapefruit juice	Avoid grapefruit juice

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. ₄ ₃
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT , is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. ₄ ₄ ₄ ₄ ₃ ₄ ₄ ₄
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. ₄
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T to T , leading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T and T levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). ₄ ₃ ₃ ₄ ₃ ₄ ₃ ₄ ₃ ₄
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of I, I, and Tc. ¹²³ ¹³¹ ^99m
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 1: Drugs that may have their plasma concentrations increased by itraconazole
Drug Class	Contraindicated	Not Recommended	Use with Caution	Comments
	Under no circumstances is the drug to be coadministered with itraconazole, and up to two weeks after discontinuation of treatment with itraconazole.	It is recommended that the use of the drug be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If coadministration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of the interacting drug is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured. The label of the coadministered drug should be consulted for information on dose adjustment and adverse effects.	Careful monitoring is recommended when the drug is coadministered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of the interacting drug, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured. The label of the coadministered drug should be consulted for information on dose adjustment and adverse effects.
Alpha Blockers		tamsulosin
Analgesics	methadone		alfentanil, buprenorphine IV and sublingual, fentanyl, oxycodone, sufentanil	Methadone: The potential increase in plasma concentrations of methadone when coadministered with SPORANOX^® may increase the risk of serious cardiovascular events including QTc prolongation and torsade de pointes.
				Fentanyl: The potential increase in plasma concentrations of fentanyl when coadministered with SPORANOX^® may increase the risk of potentially fatal respiratory depression.
				Sufentanil: No human pharmacokinetic data of an interaction with itraconazole are available. In vitro data suggest that sufentanil is metabolized by CYP3A4 and so potentially increased sufentanil plasma concentrations would be expected when coadministered with SPORANOX^®.
Antiarrhythmics	disopyramide, dofetilide, dronedarone, quinidine		digoxin	Disopyramide, dofetilide, dronedarone, quinidine: The potential increase in plasma concentrations of these drugs when coadministered with SPORANOX^® may increase the risk of serious cardiovascular events including QTc prolongation.
Antibacterials	telithromycin, in subjects with severe renal impairment or severe hepatic impairment	rifabutin	telithromycin	Telithromycin: The potential increase in plasma concentrations of telithromycin in subjects with severe renal impairment or severe hepatic impairment, when coadministered with SPORANOX^® may increase the risk of serious cardiovascular events including QT prolongation and torsade de pointes.
				Rifabutin: See also under 'Drugs that may decrease itraconazole plasma concentrations'.
Anticoagulants and Antiplatelet Drugs	ticagrelor	apixaban, rivaroxaban	coumarins, cilostazol, dabigatran	Ticagrelor: The potential increase in plasma concentrations of ticagrelor may increase the risk of bleeding.
				Coumarins: SPORANOX^® may enhance the anticoagulant effect of coumarin-like drugs, such as warfarin.
Anticonvulsants		carbamazepine		Carbamazepine: In vivo studies have demonstrated an increase in plasma carbamazepine concentrations in subjects concomitantly receiving ketoconazole. Although there are no data regarding the effect of itraconazole on carbamazepine metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of SPORANOX^® and carbamazepine may inhibit the metabolism of carbamazepine. See also under 'Drugs that may decrease itraconazole plasma concentrations'.
Antidiabetics			repaglinide, saxagliptin
Antihelmintics and Antiprotozoals			praziquantel
Antimigraine Drugs	ergot alkaloids, such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine)		eletriptan	Ergot Alkaloids: The potential increase in plasma concentrations of ergot alkaloids when coadministered with SPORANOX^® may increase the risk of ergotism, ie. a risk for vasospasm potentially leading to cerebral ischemia and/or ischemia of the extremities.
Antineoplastics	irinotecan	axitinib, dabrafenib, dasatinib, ibrutinib, nilotinib, sunitinib, trabectedin	bortezomib, busulphan, docetaxel, erlotinib, gefitinib, imatinib, ixabepilone, lapatinib, ponatinib, trimetrexate, vinca alkaloids	Irinotecan: The potential increase in plasma concentrations of irinotecan when coadministered with SPORANOX^® may increase the risk of potentially fatal adverse events.
Antipsychotics, Anxiolytics and Hypnotics	lurasidone, oral midazolam, pimozide, triazolam		alprazolam, aripiprazole, buspirone, diazepam, haloperidol, midazolam IV, perospirone, quetiapine, ramelteon, risperidone	Midazolam, triazolam: Coadministration of SPORANOX^® and oral midazolam, or triazolam may cause several-fold increases in plasma concentrations of these drugs. This may potentiate and prolong hypnotic and sedative effects, especially with repeated dosing or chronic administration of these agents.
				Pimozide: The potential increase in plasma concentrations of pimozide when coadministered with SPORANOX^® may increase the risk of serious cardiovascular events including QTc prolongation and torsade de pointes.
Antivirals		simeprevir	maraviroc, indinavir, ritonavir, saquinavir	Indinavir, ritonavir: See also under 'Drugs that may increase itraconazole plasma concentrations'.
Beta Blockers			nadolol
Calcium Channel Blockers	felodipine, nisoldipine		other dihydropyridines, verapamil	Calcium channel blockers can have a negative inotropic effect which may be additive to those of itraconazole. The potential increase in plasma concentrations of calcium channel blockers when co-administered with SPORANOX^® may increase the risk of congestive heart failure.
				Dihydropyridines: Concomitant administration of SPORANOX^® may cause several-fold increases in plasma concentrations of dihydropyridines. Edema has been reported in patients concomitantly receiving SPORANOX^® and dihydropyridine calcium channel blockers.
Cardiovascular Drugs, Miscellaneous	Ivabradine, ranolazine	aliskiren, sildenafil, for the treatment of pulmonary hypertension	bosentan, riociguat	Ivabradine: The potential increase in plasma concentrations of ivabradine when coadministered with SPORANOX® may increase the risk of ivabradine-related adverse events, such as atrial fibrillation, bradycardia, sinus arrest and heart block. Ranolazine: The potential increase in plasma concentrations of ranolazine when coadministered with SPORANOX^® may increase the risk of serious cardiovascular events including QTc prolongation.
Diuretics	eplerenone			Eplerenone: The potential increase in plasma concentrations of eplerenone when coadministered with SPORANOX^® may increase the risk of hyperkalemia and hypotension.
Gastrointestinal Drugs	cisapride		aprepitant	Cisapride: The potential increase in plasma concentrations of cisapride when coadministered with SPORANOX^® may increase the risk of serious cardiovascular events including QTc prolongation.
Immunosuppressants		everolimus, temsirolimus	budesonide, ciclesonide, cyclosporine, dexamethasone, fluticasone, methylprednisolone, rapamycin (also known as sirolimus), tacrolimus
Lipid Regulating Drugs	lovastatin, simvastatin		atorvastatin	The potential increase in plasma concentrations of atorvastatin, lovastatin, and simvastatin when coadministered with SPORANOX^® may increase the risk of skeletal muscle toxicity, including rhabdomyolysis.
Respiratory Drugs		salmeterol
Urological Drugs	fesoterodine, in subjects with moderate to severe renal impairment, or moderate to severe hepatic impairment, solifenacin, in subjects with severe renal impairment or moderate to severe hepatic impairment	darifenacin, vardenafil	fesoterodine. oxybutynin, sildenafil, for the treatment of erectile dysfunction, solifenacin, tadalafil, tolterodine	Fesoterodine: The potential increase in plasma concentrations of the fesoterodine active metabolite may be greater in subjects with moderate to severe renal impairment, or moderate to severe hepatic impairment, which may lead to an increased risk of adverse reactions.
				Solifenacin: The potential increase in plasma concentrations of solifenacin in subjects with severe renal impairment or moderate to severe hepatic impairment, when coadministered with SPORANOX^® may increase the risk of serious cardiovascular events including QT prolongation.
Other	colchicine, in subjects with renal or hepatic impairment	colchicine, conivaptan, tolvaptan	cinacalcet	Colchicine: The potential increase in plasma concentrations of colchicine when coadministered with SPORANOX^® may increase the risk of potentially fatal adverse events.
				Conivaptan and Tolvaptan: A safe and effective dose of either conivaptan or tolvaptan has not been established when coadministered with SPORANOX^®.

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Interacting DrugInteracting Drug	InteractionInteraction
Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products ( 2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents	Carefully monitor blood glucose ( 5.12, 7.3)

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 4. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 5: Established Drug Interactions Based on Studies with Didanosine Delayed-Release Capsules or Studies with Buffered Formulations of Didanosine and Expected to Occur with Didanosine Delayed-Release Capsules
Drug	Effect	Clinical Comment
↑ Indicates increase. ↓ Indicates decrease. ^aCoadministration of didanosine with food decreases didanosine concentrations. Thus, although not studied, it is possible that coadministration with heavier meals could reduce didanosine concentrations further.
ganciclovir	↑ didanosine concentration	If there is no suitable alternative to ganciclovir, then use in combination with didanosine delayed-release capsules with caution. Monitor for didanosine- associated toxicity.
methadone	↓ didanosine concentration	If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is didanosine delayed-release capsules. Patients should be closely monitored for adequate clinical response when didanosine delayed-release capsules is coadministered with methadone, including monitoring for changes in HIV RNA viral load. Do not coadminister methadone with didanosine pediatric powder due to significant decreases in didanosine concentrations.
nelfinavir	No interaction 1 hour after didanosine	Administer nelfinavir 1 hour after didanosine delayed-release capsules.
tenofovir disoproxil fumarate	↑ didanosine concentration	A dose reduction of didanosine delayed-release capsules to the following dosage once daily taken together with tenofovir disoproxil fumarate and a light meal (400 kcalories or less and 20% fat or less) or in the fasted state is recommended.^a 250 mg (adults weighing at least 60 kg with creatinine clearance of at least 60 mL/min) 200 mg (adults weighing less than 60 kg with creatinine clearance of at least 60 mL/min) Patients should be monitored for didanosine-associated toxicities and clinical response.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 2: Drug Interactions: Pharmacokinetic Parameters for Indinavir in the Presence of the Coadministered Drug (See PRECAUTIONS, Table 9 for Recommended Alterations in Dose or Regimen)
Coadministered drug	Dose of Coadministered drug (mg)	Dose of CRIXIVAN (mg)	n	Ratio (with/without coadministered drug) of Indinavir Pharmacokinetic Parameters (90% CI); No Effect = 1.00
				C_max	AUC	C_min
All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
Cimetidine	600 twice daily, 6 days	400 single dose	12	1.07 (0.77, 1.49)	0.98 (0.81, 1.19)	0.82 (0.69, 0.99)
Clarithromycin	500 q12h, 7 days	800 three times daily, 7 days	10	1.08 (0.85, 1.38)	1.19 (1.00, 1.42)	1.57 (1.16, 2.12)
Delavirdine	400 three times daily	400 three times daily, 7 days	28	0.64Relative to indinavir 800 mg three times daily alone. (0.48, 0.86)	No significant change	2.18 (1.16, 4.12)
Delavirdine	400 three times daily	600 three times daily, 7 days	28	No significant change	1.53 (1.07, 2.20)	3.98 (2.04, 7.78)
EfavirenzStudy conducted in HIV-positive subjects.	600 once daily, 10 days	1000 three times daily, 10 days	20
		After morning dose		No significant change	0.67 (0.61, 0.74)	0.61 (0.49, 0.76)
		After afternoon dose		No significant change	0.63 (0.54, 0.74)	0.48 (0.43, 0.53)
		After evening dose		0.71 (0.57, 0.89)	0.54 (0.46, 0.63)	0.43 (0.37, 0.50)
Fluconazole	400 once daily, 8 days	1000 three times daily, 7 days	11	0.87 (0.72, 1.05)	0.76 (0.59, 0.98)	0.90 (0.72, 1.12)
Grapefruit Juice	8 oz.	400 single dose	10	0.65 (0.53, 0.79)	0.73 (0.60, 0.87)	0.90 (0.71, 1.15)
Isoniazid	300 once daily in the morning, 8 days	800 three times daily, 7 days	11	0.95 (0.88, 1.03)	0.99 (0.87, 1.13)	0.89 (0.75, 1.06)
Itraconazole	200 twice daily, 7 days	600 three times daily, 7 days	12	0.78 (0.69, 0.88)	0.99 (0.91, 1.06)	1.49 (1.28, 1.74)
Ketoconazole	400 once daily, 7 days	600 three times daily, 7 days	12	0.69 (0.61, 0.78)	0.80 (0.74, 0.87)	1.29 (1.11, 1.51)
	400 once daily, 7 days	400 three times daily, 7 days	12	0.42 (0.37, 0.47)	0.44 (0.41, 0.48)	0.73 (0.62, 0.85)
Methadone	20-60 once daily in the morning, 8 days	800 three times daily, 8 days	10	See text below for discussion of interaction.
Quinidine	200 single dose	400 single dose	10	0.96 (0.79, 1.18)	1.07 (0.89, 1.28)	0.93 (0.73, 1.19)
Rifabutin	150 once daily in the morning, 10 days	800 three times daily, 10 days	14	0.80 (0.72, 0.89)	0.68 (0.60, 0.76)	0.60 (0.51, 0.72)
Rifabutin	300 once daily in the morning, 10 days	800 three times daily, 10 days	10	0.75 (0.61, 0.91)	0.66 (0.56, 0.77)	0.61 (0.50, 0.75)
Rifampin	600 once daily in the morning, 8 days	800 three times daily, 7 days	12	0.13 (0.08, 0.22)	0.08 (0.06, 0.11)	Not Done
Ritonavir	100 twice daily, 14 days	800 twice daily, 14 days	10, 16Comparison to historical data on 16 subjects receiving indinavir alone.	See text below for discussion of interaction.
Ritonavir	200 twice daily, 14 days	800 twice daily,14 days	9, 16	See text below for discussion of interaction.
Sildenafil	25 single dose	800 three times daily	6	See text below for discussion of interaction.
St. John's wort (Hypericum perforatum, standardized to 0.3 % hypericin)	300 three times daily with meals, 14 days	800 three times daily	8	Not Available	0.46 (0.34, 0.58)95% CI.	0.19 (0.06, 0.33)
Stavudine (d4T)	40 twice daily, 7 days	800 three times daily, 7 days	11	0.95 (0.80, 1.11)	0.95 (0.80, 1.12)	1.13 (0.83, 1.53)
Trimethoprim/ Sulfamethoxazole	800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days	400 four times daily, 7 days	12	1.12 (0.87, 1.46)	0.98 (0.81, 1.18)	0.83 (0.72, 0.95)
Zidovudine	200 three times daily, 7 days	1000 three times daily, 7 days	12	1.06 (0.91, 1.25)	1.05 (0.86, 1.28)	1.02 (0.77, 1.35)
Zidovudine/ Lamivudine (3TC)	200/150 three times daily, 7 days	800 three times daily, 7 days	6, 9Parallel group design; n for indinavir + coadministered drug, n for indinavir alone.	1.05 (0.83, 1.33)	1.04 (0.67, 1.61)	0.98 (0.56, 1.73)

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Table 18. Summary of Effect of Co-administered Drugs on Exposure to Active Moiety (Risperidone + 9- Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Co-administered Drug	Dosing Schedule		Effect on Active Moeity (Risperidone + 9-Hydroxy-Risperidone (RatioChange relative to reference)		Risperidone Dose Recommendation
	Co-administered Drug	Risperidone	AUC	C_max
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Table 25: Clinically Important Drug Interactions with Aripiprazole:
Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aipiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.8)].
Benzodiazepines (e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.8)]	Monitor sedation and blood pressure. Adjust dose accordingly.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, and nefazodone), Erythromycin	Contraindicated with lovastatin
Gemfibrozil, cyclosporine	Avoid with lovastatin
Danazol, diltiazem, dronedarone, verapamil	Do not exceed 20 mg lovastatin daily
Amiodarone	Do not exceed 40 mg lovastatin daily
Grapefruit juice	Avoid grapefruit juice

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir), Hepatitis C Protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Oral drugs that have to be separated from Phoslyra
	Dosing Recommendations
Flouroquinolones	Take at least 2 hours before or 6 hours after Phoslyra
Tetracyclines	Take at least 1 hour before Phoslyra
Levothyroxine	Take at least 4 hours before or 4 hours after Phoslyra

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Table II. Clinically significant drug interactions with theophylline*.
Drug	Type of Interaction	Effect^**
* Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
** Average effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions.
Individual patients may experience larger changes in serum theophylline concentration than the value listed
Adenosine	Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.
Alcohol	A single large dose of alcohol (3 ml/kg of whiskey) decreases theophylline clearance for up to 24 hours.	30% increase
Allopurinol	Decreases theophylline clearance at allopurinol doses ≥600 mg/day.	25% increase
Aminoglutethimide	Increases theophylline clearance by induction of microsomal enzyme activity.	25% decrease
Carbamazepine	Similar to aminoglutethimide	30% decrease
Cimetidine	Decreases theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase
Ciprofloxacin	Similar to cimetidine.	40% increase
Clarithromycin	Similar to erythromycin.	25% increase
Diazepam	Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.	Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram	Decreases theophylline clearance by inhibiting hydroxylation and demethylation.	50% increase
Enoxacin	Similar to cimetidine.	300% increase
Ephedrine	Synergistic CNS effects	Increased frequency of nausea, nervousness, and insomnia.
Erythromycin	Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen	Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.	30% increase
Flurazepam	Similar to diazepam.	Similar to diazepam.
Fluvoxamine	Similar to cimetidine	Similar to cimetidine
Halothane	Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.	Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A	Decreases theophylline clearance.	100% increase
Isoproterenol (IV)	Increases theophylline clearance.	20% decrease
Ketamine	Pharmacologic	May lower theophylline seizure threshold.
Lithium	Theophylline increases renal lithium clearance.	Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam	Similar to diazepam.	Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.	20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine	Similar to disulfiram.	80% increase
Midazolam	Similar to diazepam.	Similar to diazepam.
Moricizine	Increases theophylline clearance.	25% decrease
Pancuronium	Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.	Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline	Decreases theophylline clearance.	30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.	25% decrease after two weeks of concurrent PB.
Phenytoin	Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.	Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone	Decreases theophylline clearance and pharmacologic interaction.	40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and pharmacologic interaction.	100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin	Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.	20-40% decrease
Sulfinpyrazone	Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.	20% decrease
Tacrine	Similar to cimetidine, also increases renal clearance of theophylline.	90% increase
Thiabendazole	Decreases theophylline clearance.	190% increase
Ticlopidine	Decreases theophylline clearance.	60% increase
Troleandomycin	Similar to erythromycin.	33-100% increase depending on troleandomycin dose.
Verapamil	Similar to disulfiram.	20% increase

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin	Monitor phenytoin level (7)
Methotrexate	Monitor for methotrexate toxicity (7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( 7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( 7)
Phenytoin	Monitor phenytoin level ( 7)
Methotrexate	Monitor for methotrexate toxicity ( 7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine ( 7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin ( 7)

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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Table 6: Predicted Drug Interactions with Didanosine Delayed-Release Capsules
↑ Indicates increase.
Drug or Drug Class	Effect	Clinical Comment
Drugs that may cause pancreatic toxicity	↑risk of pancreatitis	Use only with extreme caution.
Neurotoxic drugs	↑risk of neuropathy	Use with caution.

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Increased Risk of Myopathy/Rhabdomyolysis (2, 5.1, 7, 12.3)
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
Lopinavir plus ritonavir	Use lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( 7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( 7)
Phenytoin	Monitor phenytoin level ( 7)
Methotrexate	Monitor for methotrexate toxicity ( 7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine ( 7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin ( 7)

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine concentrations approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
	? carbamazepine epoxide	May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Table 3 Established and Other Potentially SignificantThis table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
Concomitant Drug Class: Drug Name	Effect	Clinical Comment
HIV antiviral agents
Protease inhibitor: atazanavir	↓atazanavir ↑ tenofovir	Coadministration of atazanavir with ATRIPLA is not recommended. Coadministration of atazanavir with either efavirenz or tenofovir DF decreases plasma concentrations of atazanavir. The combined effect of efavirenz plus tenofovir DF on atazanavir plasma concentrations is not known. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA.
Protease inhibitor: fosamprenavir calcium	↓ amprenavir	Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and ATRIPLA with respect to safety and efficacy have not been established. Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when ATRIPLA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when ATRIPLA is administered with fosamprenavir plus ritonavir twice daily.
Protease inhibitor: indinavir	↓ indinavir	The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz.
Protease inhibitor: lopinavir/ritonavir	↓ lopinavir ↑ tenofovir	Do not use once daily administration of lopinavir/ritonavir. Dose increase of lopinavir/ritonavir is recommended for all patients when coadministered with efavirenz. Refer to the full prescribing information for lopinavir/ritonavir for guidance on coadministration with efavirenz- or tenofovir-containing regimens, such as ATRIPLA. Patients should be monitored for tenofovir-associated adverse reactions.
Protease inhibitor: ritonavir	↑ ritonavir ↑ efavirenz	When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when ATRIPLA is used in combination with ritonavir.
Protease inhibitor: saquinavir	↓ saquinavir	Appropriate doses of the combination of efavirenz and saquinavir/ritonavir with respect to safety and efficacy have not been established.
CCR5 co-receptor antagonist: maraviroc	↓ maraviroc	Efavirenz decreases plasma concentrations of maraviroc. Refer to the full prescribing information for maraviroc for guidance on coadministration with ATRIPLA.
NRTI: didanosine	↑ didanosine	Coadministration of ATRIPLA and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions including pancreatitis, lactic acidosis, and neuropathy. A dose reduction of didanosine is recommended when coadministered with tenofovir DF. For additional information on coadministration with tenofovir DF-containing products, please refer to the didanosine prescribing information.
NNRTI: Other NNRTIs	↑ or ↓ efavirenz and/or NNRTI	Combining two NNRTIs has not been shown to be beneficial. ATRIPLA contains efavirenz and should not be coadministered with other NNRTIs.
Integrase strand transfer inhibitor: raltegravir	↓ raltegravir	Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
Hepatitis C antiviral agents
Protease inhibitor: boceprevir	↓ boceprevir	Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with efavirenz, which may result in loss of therapeutic effect. The combination should be avoided.
Protease inhibitor: simeprevir	↓ simeprevir ↔ efavirenz	Concomitant administration of simeprevir with efavirenz is not recommended because it may result in loss of therapeutic effect of simeprevir.
NS5A inhibitor/NS5B polymerase inhibitor : ledipasvir/sofosbuvir	↑ tenofovir	Patients receiving ATRIPLA and HARVONI^® (ledipasvir/sofosbuvir) concomitantly should be monitored for adverse reactions associated with tenofovir DF.
Other agents
Anticoagulant: warfarin	↑ or ↓ warfarin	Plasma concentrations and effects potentially increased or decreased by efavirenz.
Anticonvulsants: carbamazepine	↓ carbamazepine ↓ efavirenz	There are insufficient data to make a dose recommendation for ATRIPLA. Alternative anticonvulsant treatment should be used.
phenytoin phenobarbital	↓ anticonvulsant ↓ efavirenz	Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
Antidepressants: bupropion	↓ buproprion	The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded.
sertraline	↓ sertraline	Increases in sertraline dose should be guided by clinical response.
Antifungals: itraconazole	↓ itraconazole ↓ hydroxy-itraconazole	Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
ketoconazole	↓ ketoconazole	Drug interaction trials with ATRIPLA and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole.
posaconazole	↓ posaconazole	Avoid concomitant use unless the benefit outweighs the risks.
Anti-infective: clarithromycin	↓ clarithromycin ↑ 14-OH metabolite	Clinical significance unknown. In uninfected volunteers, 46% developed rash while receiving efavirenz and clarithromycin. No dose adjustment of ATRIPLA is recommended when given with clarithromycin. Alternatives to clarithromycin, such as azithromycin, should be considered. Other macrolide antibiotics, such as erythromycin, have not been studied in combination with ATRIPLA.
Antimycobacterial: rifabutin	↓ rifabutin	Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
rifampin	↓ efavirenz	If ATRIPLA is coadministered with rifampin to patients weighing 50 kg or more, an additional 200 mg/day of efavirenz is recommended.
Antimalarials: artemether/lumefantrine	↓ artemether ↓ dihydroartemisinin ↓ lumefantrine	Artemether/lumefantrine should be used cautiously with ATRIPLA because decreased artemether, dihydroartemisinin (active metabolite of artemether), and/or lumefantrine concentrations may result in a decrease of antimalarial efficacy of artemether/lumefantrine.
Calcium channel blockers: diltiazem	↓ diltiazem ↓ desacetyl diltiazem ↓ N-monodes-methyl diltiazem	Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of ATRIPLA is necessary when administered with diltiazem.
Others (e.g., felodipine, nicardipine, nifedipine, verapamil)	↓ calcium channel blocker	No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker).
HMG-CoA reductase inhibitors: atorvastatin pravastatin simvastatin	↓ atorvastatin ↓ pravastatin ↓ simvastatin	Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with efavirenz. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
Hormonal contraceptives:
Oral: ethinyl estradiol/norgestimate	↓ active metabolites of norgestimate	A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed.
Implant: etonogestrel	↓ etonogestrel	A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.
Immunosuppressants: cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A	↓ immuno-suppressant	Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by efavirenz. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with ATRIPLA.
Narcotic analgesic: methadone	↓ methadone	Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.

Table name: Octreotide Tolbutamide Radiographic contrast agents) Sucralfate Tamoxifen Slow-Release Nicotinic Acid Salicylates (> 2 g/day) Rifampin Propylthiouracil (PTU) - Indandione Derivatives (SSRIs; e.g., Sertraline) - Insulin - Somatropin - (e.g., Theophylline) Thiazide Diuretics


Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion – the reduction is not sustained;therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids
Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( > 1 µg/kg/min); Glucocorticoids (hydrocortisone > 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides
Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T ₄ and T ₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing
Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat
Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane
Androgens / Anabolic Steroids Asparaginase Glucocorticoids
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone
Administration of these agents with levothyroxine results in an initial transient increase in FT ₄. Continued administration results in a decrease in serum T ₄ and normal FT ₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T ₄ and T ₃ to TBG and transthyretin. An initial increase in serum FT4 is followed by return of FT ₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T ₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital
Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T ₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5’-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone > 4 mg/day)
Administration of these enzyme inhibitors decreases the peripheral conversion of T ₄ to T ₃, leading to decreased T ₃ levels. However, serum T ₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T ₃ and T ₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T ₃ concentrations by 30% with minimal change in serum T ₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T ₃ and T ₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives
Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors
Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones
Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Growth Hormones - Somatrem
Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators
Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ⁹⁹mTc
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use)
These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.

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Table 7: Summary of AED Interactions with Oxcarbazepine
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400 to 2,000	900	nc nc denotes a mean change of less than 10%	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100 to 150	600 to 1,800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250 to 500	600 to 1,800 >1,200 to 2,400	nc Pediatrics up to 40% increase Mean increase in adults at high oxcarbazepine doses [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400 to 2,800	600 to 1,800	nc	18% decrease [CI: 13% decrease, 40% decrease]

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( 7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( 7)
Phenytoin	Monitor phenytoin level ( 7)
Methotrexate	Monitor for methotrexate toxicity ( 7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine ( 7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin tablets absorption. Take 2 hours before or 6 hours after ciprofloxacin tablets ( 7)

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Table 14: Clinically Important Drug Interactions: Effect of Other Drugs on Guanfacine Extended-Release Tablets
Concomitant Drug Name or Drug Class	Clinical Rationale and Magnitude of Drug Interaction	Clinical Recommendation
Strong and moderate CYP3A4 inhibitors, e.g., ketoconazole, fluconazole	Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in an increase in exposure	Consider dose reduction [see Dosage and Administration (2.7) ]
Strong and moderate CYP3A4 inducers, e.g., rifampin, efavirenz	Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in a decrease in exposure	Consider dose increase [see Dosage and Administration (2.7) ]

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Factors	Dosage Adjustment of aripiprazole
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP2D6 CYP3A4 inhibitors or	Administer half of usual dose
Strong CYP2D6 CYP3A4 inhibitors and	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double usual dose over 1 to 2 weeks

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.*
* Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol, systemic and inhaled	hydrocortisone	ofloxacin
amoxicillin	isoflurane	omeprazole
ampicillin, with or without	isoniazid	prednisone, prednisolone
sulbactam	isradipine	ranitidine
atenolol	influenza vaccine	rifabutin
azithromycin	ketoconazole	roxithromycin
caffeine, dietary ingestion	lomefloxacin	sorbitol
cefaclor	mebendazole	(purgative doses do
co-trimoxazole (trimethoprim	medroxyprogesterone	not inhibit theophylline
and sulfamethoxazole)	methylprednisolone	absorption)
diltiazem	metronidazole	sucralfate
dirithromycin	metoprolol	terbutaline,systemic
enflurane	nadolol	terfenadine
famotidine	nifedipine	tetracycline
felodipine	nizatidine	tocainide
finasteride	norfloxacin

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg. ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓levonorgestrel	Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.8)].
Benzodiazepines (e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.8)]	Monitor sedation and blood pressure. Adjust dose accordingly.

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( 7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( 7)
Phenytoin	Monitor phenytoin level ( 7)
Methotrexate	Monitor for methotrexate toxicity ( 7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine ( 7)
Multivalent cation-containing products including antacids, metal cations, or didanosine	Decreased Ciprofloxacin absorption. Take 2 hours before or 6 hours after Ciprofloxacin ( 7)

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Table 7: Summary of AED Interactions with Oxcarbazepine
¹nc denotes a mean change of less than 10%
²Pediatrics
³Mean increase in adults at high oxcarbazepine doses
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400 to 2000	900	nc ¹	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100 to150	600 to 1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250 to 500	600 to 1800 >1200 to 2400	nc ^1,2 up to 40% increase ³ [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400 to 2800	600 to 1800	nc ¹	18% decrease [CI: 13% decrease, 40% decrease]
Lamotrigine	200	1200	nc ¹	nc ¹

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Antibiotics	Antineoplastics	Anti-inflammatory Drugs	Gastrointestinal Agents
ciprofloxacin	melphalan	azapropazon	cimetidine
gentamicin		colchicine	ranitidine
tobramycin	Antifungals	diclofenac
vancomycin	amphotericin B	naproxen	Immunosuppressives
trimethoprim with sulfamethoxazole	ketoconazole	sulindac	tacrolimus

			Other Drugs
			fibric acid derivatives
			(e.g.,bezafibrate, fenofibrate) methotrexate

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Drugs That Interfere with Hemostasis
Clinical Impact:	Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of diclofenac sodium topical gel with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions (5.2)].
Intervention:	Concomitant use of diclofenac sodium topical gel and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions (5.11)]. Diclofenac sodium topical gel is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol) In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of diclofenac sodium topical gel and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of diclofenac sodium topical gel and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of diclofenac sodium topical gel with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact:	The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of diclofenac sodium topical gel and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of diclofenac sodium topical gel and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of diclofenac sodium topical gel and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of diclofenac sodium topical gel and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention:	During concomitant use of diclofenac sodium topical gel and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions (5.2)].
Intervention:	The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of diclofenac sodium topical gel and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of diclofenac sodium topical gel and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and Gl toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.

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Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs that Interfere with Hemostasis
Clinical Impact :	Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention :	Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions ( 5 . 11)].
Aspirin
Clinical Impact :	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions ( 5 . 2)].
Intervention :	Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions ( 5 . 11)]. Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors , Angiotensin Receptor Blockers , or Beta - Blockers
Clinical Impact :	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention :	During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions ( 5 . 6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact :	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention :	During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions ( 5 . 6)].
Lithium
Clinical Impact :	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology ( 12 . 3)].
Intervention :	During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact :	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention :	During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact :	Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention :	During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact :	Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions ( 5 . 2)].
Intervention :	The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact :	Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention :	During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name:

Drugs That Interfere with Hemostasis
Clinical Impact:	· Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. · Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11) ].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions ( 5.2 ) ].
Intervention:	Concomitant use of naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11) ]. Naproxen sodium is not substitutes for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	· NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). · In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment,co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	· During concomitant use of naproxen sodium and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. · During concomitant use of naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions ( 5.6 ) ]. · When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions ( 5.6 ) ].
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin
Intervention:	During concomitant use of naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions ( 5.2 ) ].
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen sodium is not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxen sodium is not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:	Patients simultaneously receiving naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

Table name:

Table 3: Clinically Significant drug interactions with Celecoxib
Drugs That Interfere with Hemostasis
Clinical Impact:	Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of Celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of celecoxib capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions ( 5.2 )]. In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200-400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100-325 mg).
Intervention:	Concomitant use of celecoxib capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Celecoxib capsules are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of celecoxib capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of celecoxib capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of celecoxib capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact:	The concomitant use of Celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of celecoxib capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of celecoxib capsules and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Celecoxib has no effect on methotrexate pharmacokinetics.
Intervention:	During concomitant use of celecoxib capsules and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of celecoxib capsules and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of celecoxib capsules and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention:	The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of celecoxib capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of celecoxib capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or inducers
Clinical Impact:	Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Coadministration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib.
Intervention:	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [see Clinical Pharmacology (12.3)].
CYP2D6 substrates
Clinical Impact:	In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs.
Intervention:	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [see Clinical Pharmacology (12.3)].
Corticosteroids
Clinical Impact:	Concomitant use of corticosteroids with celecoxib capsules may increase the risk of GI ulceration or bleeding.
Intervention:	Monitor patients with concomitant use of celecoxib capsules with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)].

Table name:

Antibiotics	Anticonvulsants	Other Drugs/DietarySupplements
nafcillin	carbamazepine	bosentan	St. John’s Wort
rifampin	oxcarbazepine	octreotide
	phenobarbital	orlistat
	phenytoin	sulfinpyrazone
		terbinafine
		ticlopidine

Table name:

Antibiotics	Anticonvulsants	Other Drugs/Dietary Supplements
nafcillin	carbamazepine	bosentan
rifampin	oxcarbazepine	octreotide
	phenobarbital	orlistat
	phenytoin	sulfinpyrazone
		St. John's Wort
		terbinafine
		ticlopidine

Table name:


^a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
^b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

Table name:

Drugs that Affect Renal Function	A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics	Dofetilide	Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
	Sotalol	Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
	Dronedarone	Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog	Teriparatide	Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement	Thyroid	Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics	Epinephrine Norepinephrine Dopamine	Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents	Succinylcholine	May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements	Calcium	If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers		Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.
Hyperpolarization-activated cyclic nucleotide-gated channel blocker	Ivabradine	Can increase the risk of bradycardia

Table name:

Table 9: Clinically Important Drug Interactions with VRAYLAR
Strong CYP3A4 Inhibitors
Clinical Impact:	Concomitant use of VRAYLAR with a strong CYP3A4 inhibitor increases the exposures of cariprazine and its major active metabolite, didesmethylcariprazine (DDCAR), compared to use of VRAYLAR alone [see Clinical Pharmacology (12.3)].
Intervention:	If VRAYLAR is used with a strong CYP3A4 inhibitor, reduce VRAYLAR dosage [see Dosage and Administration (2.3)].
Examples:	itraconazole, ketoconazole
CYP3A4 Inducers
Clinical Impact:	CYP3A4 is responsible for the formation and elimination of the active metabolites of cariprazine. The effect of CYP3A4 inducers on the exposure of VRAYLAR has not been evaluated, and the net effect is unclear [see Clinical Pharmacology (12.3)].
Intervention:	Concomitant use of VRAYLAR with a CYP3A4 inducer is not recommended [see Dosage and Administration (2.1, 2.3)].
Examples:	rifampin, carbamazepine

Table name: Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.During concomitant use of diclofenac sodium delayed-release tablets and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of diclofenac sodium delayed-release tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS: Renal Toxicity and Hyperkalemia ). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.

Table 2. Clinically Significant Drug Interactions with Diclofenac
Drugs That Interfere with Hemostasis
Clinical Impact:
Intervention:	Monitor patients with concomitant use of diclofenac sodium delayed-release tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS: Hematologic Toxicity ).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ).
Intervention:	Concomitant use of diclofenac sodium delayed-release tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS: Hematologic Toxicity ). Diclofenac sodium delayed-release tablets are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:
Intervention:
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS: Renal Toxicity and Hyperkalemia ).
Digoxin
Clinical Impact:	The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of diclofenac sodium delayed-release tablets and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ).
Intervention:	The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of diclofenac sodium delayed-release tablets and pemetrexed may increase the risk of pemetrexed‑ associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or Inducers:
Clinical Impact:	Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Co-administration of diclofenac with CYP2C9 inhibitors (e.g. voriconazole) may enhance the exposure and toxicity of diclofenac whereas co‑administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of diclofenac.
Intervention:	A dosage adjustment may be warranted when diclofenac is administered with CYP2C9 inhibitors or inducers (see CLINICAL PHARMACOLOGY: Pharmacokinetics ).

Table name:

Factors	Dosage Adjustment of Aripiprazole tablets
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors	Administer half of usual dose
Strong CYP2D6 andCYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double usual dose over 1 to 2 weeks

Table name:

Digoxin concentrations increased greater than 50%
	Digoxin Serum Concentration Increase	Digoxin AUC Increase	Recommendations
Quinidine	NA	54-83%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
Ritonavir	NA	86%
Digoxin concentrations increased less than 50%
Amiodarone	17%	40%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
Propafenone	28%	29%
Quinine	NA	34-38%
Spironolactone	NA	44%
Verapamil	NA	24%

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.10, 7.3)

Table name:

Antibiotics	Antineoplastic	Antifungals	Anti- Inflammatory Drugs	Gastrointestinal Agents	Immunosuppressives	Other Drugs
ciprofloxacingentamicin tobramycin trimethoprim with sulfamethoxazole vancomycin	melphalan	amphotericin Bketoconazole	azapropazoncolchicine diclofenacnaproxen sulindac	cimetidine ranitidine	tacrolimus	fibric acid derivatives (e.g., bezafibrate, fenofibrate) methotrexate

Table name:

Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate[see Warnings and Precautions (5.6).]
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [see Adverse Reactions (6.1).]
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution 2-fold increase in exposure	Monitor for sildenafil toxicity (see Pharmacokinetics -(12.3)-].
Duloxetine	Avoid Use 5-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx^® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2)].	Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

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Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio Change relative to reference )		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	C_max	Risperidone Dose Recommendation
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 mg or 3 mg twice daily	1.4	1.5	Reevaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	--	Reevaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	--
	40 mg/day -	4 mg/day	1.8	--
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Table 8: Clinically Significant Drug Interactions with Clarithromycin
Drugs That Are Affected By Clarithromycin
Drug(s) with Pharmacokinetics Affected by Clarithromycin		Recommendation	Comments
Antiarrhythmics: Disopyramide Quinidine Dofetilide Amiodarone Sotalol Procainamide Digoxin		Not Recommended Use With Caution	Disopyramide, Quinidine: There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs [see Warnings and Precautions (5.3)] . Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine. There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide. Digoxin: Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are co-administered, inhibition of Pgp by clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range.
Oral Anticoagulants: Warfarin		Use With Caution	Oral anticoagulants: Spontaneous reports in the postmarketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously [see Warnings and Precautions (5.4)] .
Antiepileptics: Carbamazepine		Use With Caution	Carbamazepine: Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered. Increased serum concentrations of carbamazepine were observed in clinical trials with clarithromycin. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with carbamazepine.
Antifungals: Itraconazole Fluconazole		Use With Caution No Dose Adjustment	Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly (see also Itraconazole under “Drugs That Affect Clarithromycin” in the table below). Clarithromycin may increase the plasma concentrations of itraconazole. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions. Fluconazole: [see Pharmacokinetics (12.3)]
Anti-Gout Agents: Colchicine (in patients with renal or hepatic impairment) Colchicine (in patients with normal renal and hepatic function)		Contraindicated Use With Caution	Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. The dose of colchicine should be reduced when co-administered with clarithromycin in patients with normal renal and hepatic function [see Contraindications (4.4) and Warnings and Precautions (5.4)] .
Antipsychotics: Pimozide Quetiapine		Contraindicated	Pimozide: [See Contraindications (4.2)] Quetiapine: Quetiapine is a substrate for CYP3A4, which is inhibited by clarithromycin. Co-administration with clarithromycin could result in increased quetiapine exposure and possible quetiapine related toxicities. There have been postmarketing reports of somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation during concomitant administration. Refer to quetiapine prescribing information for recommendations on dose reduction if co-administered with CYP3A4 inhibitors such as clarithromycin.
Antispasmodics: Tolterodine (patients deficient in CYP2D6 activity)		Use With Caution	Tolterodine: The primary route of metabolism for tolterodine is via. CYP2D6. However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via. CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when co-administered with clarithromycin.
Antivirals: Atazanavir Saquinavir (in patients with decreased renal function) Ritonavir Etravirine Maraviroc Boceprevir (in patients with normal renal function) Didanosine Zidovudine		Use With Caution No Dose Adjustment	Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)] . Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction (see Saquinavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)] . Ritonavir, Etravirine: (see Ritonavir and Etravirine under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)] . Maraviroc : Clarithromycin may result in increases in maraviroc exposures by inhibition of CYP3A metabolism. See Selzentry ^® prescribing information for dose recommendation when given with strong CYP3A inhibitors such as clarithromycin. Boceprevir: Both clarithromycin and boceprevir are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when co-administered. No dose adjustments are necessary for patients with normal renal function (see Victrelis ^® prescribing information). Zidovudine: Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Administration of clarithromycin and zidovudine should be separated by at least two hours [see Pharmacokinetics (12.3)] .
Calcium Channel Blockers: Verapamil Amlodipine Diltiazem Nifedipine		Use With Caution	Verapamil: Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, [see Warnings and Precautions (5.4)] . Amlodipine, Diltiazem: [See Warnings and Precautions (5.4)] Nifedipine: Nifedipine is a substrate for CYP3A. Clarithromycin and other macrolides are known to inhibit CYP3A. There is potential of CYP3A-mediated interaction between nifedipine and clarithromycin. Hypotension and peripheral edema were observed when clarithromycin was taken concomitantly with nifedipine [see Warnings and Precautions (5.4)] .
Ergot Alkaloids: Ergotamine Dihydroergotamine		Contraindicated	Ergotamine, Dihydroergotamine: Postmarketing reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4.6)].
Gastroprokinetic Agents: Cisapride		Contraindicated	Cisapride: [See Contraindications (4.2)]
HMG-CoA Reductase Inhibitors: Lovastatin Simvastatin Atorvastatin Pravastatin Fluvastatin		Contraindicated Use With Caution No Dose Adjustment	Lovastatin, Simvastatin, Atorvastatin, Pravastatin, Fluvastatin: [See Contraindications (4.5) and Warnings and Precautions (5.4)]
Hypoglycemic Agents: Nateglinide Pioglitazone Repaglinide Rosiglitazone Insulin		Use With Caution	Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)] Insulin: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]
Immunosuppressants: Cyclosporine Tacrolimus		Use With Caution	Cyclosporine: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine. Tacrolimus: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with tacrolimus.
Phosphodiesterase inhibitors: Sildenafil Tadalafil Vardenafil		Use With Caution	Sildenafil, Tadalafil, Vardenafil: Each of these phosphodiesterase inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant administration of clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil, or vardenafil will result in increased exposure of these phosphodiesterase inhibitors. Co-administration of these phosphodiesterase inhibitors with clarithromycin is not recommended. Increased systemic exposure of these drugs may occur with clarithromycin; reduction of dosage for phosphodiesterase inhibitors should be considered (see their respective prescribing information).
Proton Pump Inhibitors: Omeprazole		No Dose Adjustment	Omeprazole: The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when coadministered with clarithromycin as a result of increased omeprazole exposures [see Pharmacokinetics (12.3)] (see also Omeprazole under “Drugs That Affect Clarithromycin” in the table below).
Xanthine Derivatives: Theophylline		Use With Caution	Theophylline: Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations [see Pharmacokinetics (12.3)] . Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range.
Triazolobenzodiazepines and Other Related Benzodiazepines: Midazolam Alprazolam Triazolam Temazepam Nitrazepam Lorazepam		Use With Caution No Dose Adjustment	Midazolam: When oral midazolam is co-administered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated [see Warnings and Precautions (5.4) and Pharmacokinetics (12.3)] . Triazolam, Alprazolam: Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is co-administered with clarithromycin. There have been postmarketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested. In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines. Temazepam, Nitrazepam, Lorazepam: For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.
Cytochrome P450 Inducers: Rifabutin		Use With Caution	Rifabutin: Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis (see Rifabutin under “Drugs That Affect Clarithromycin” in the table below).
Other Drugs Metabolized by CYP3A: Alfentanil Bromocriptine Cilostazol Methylprednisole Vinblastine Phenobarbital St. John’s Wort		Use With Caution	There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort.
Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A: Hexobarbital Phenytoin Valproate		Use With Caution	There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.
Drugs that Affect Clarithromycin
Drug(s) that Affect the Pharmacokinetics of Clarithromycin	Recommendation		Comments
Antifungals: Itraconazole	Use With Caution		Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions (see also Itraconazole under “Drugs That Are Affected By Clarithromycin” in the table above).
Antivirals: Atazanavir Ritonavir (in patients with decreased renal function) Saquinavir (in patients with decreased renal function) Etravirine Saquinavir (in patients with normal renal function) Ritonavir (in patients with normal renal function)	Use With Caution No Dose Adjustment		Atazanavir: When clarithromycin is co-administered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology (12.3)] . Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors. Ritonavir: Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with ritonavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium [see Pharmacokinetics (12.3)] . Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors. Saquinavir: When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (refer to ritonavir above) [see Pharmacokinetics (12.3)] . Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.
Proton Pump Inhibitors: Omeprazole	Use With Caution		Omeprazole: Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole [see Pharmacokinetics (12.3)] .
Miscellaneous Cytochrome P450 Inducers: Efavirenz Nevirapine Rifampicin Rifabutin Rifapentine	Use With Caution		Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are Affected By Clarithromycin” in the table above).

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Table 4. Drugs That May Alter Hepatic Metabolism of T4 (Hypothyroidism)
Potential impact: Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased SYNTHROID requirements.
Drug or Drug Class	Effect
Phenobarbital Rifampin	Phenobarbital has been shown to reduce the response to thyroxine. Phenobarbital increases L-thyroxine metabolism by inducing uridine 5’-diphospho-glucuronosyltransferase (UGT) and leads to a lower T4 serum levels. Changes in thyroid status may occur if barbiturates are added or withdrawn from patients being treated for hypothyroidism. Rifampin has been shown to accelerate the metabolism of levothyroxine.

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Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.6).]
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported . Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [see Adverse Reactions (6.1).]
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution 2-fold increase in exposure	Monitor for sildenafil toxicity (see Pharmacokinetics -(12.3)-] .
Duloxetine	Avoid Use 5-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx ^® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2)].	Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

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Table 4 Drugs Tested in In Vitro Binding or In Vivo Drug Interaction Testing or With Post-Marketing Reports
^a Should be administered at least 4 hours prior to WELCHOL
^b No significant alteration of warfarin drug levels with warfarin and WELCHOL coadministration in an in vivo study which did not evaluate warfarin pharmacodynamics (INR). [See Post-marketing Experience (6.2)]
^c Cyclosporine levels should be monitored and, based on theoretical grounds, cyclosporine should be administered at least 4 hours prior to WELCHOL.
Drugs with a known interaction with colesevelam	Cyclosporine^c, glyburide^a, levothyroxine^a, and oral contraceptives containing ethinyl estradiol and norethindrone^a
Drugs with postmarketing reports consistent with potential drug-drug interactions when coadministered with WELCHOL	phenytoin^a, warfarin^b
Drugs that do not interact with colesevelam based on in vitro or in vivo testing	cephalexin, ciprofloxacin, digoxin, warfarin^b fenofibrate, lovastatin, metformin, metoprolol, pioglitazone, quinidine, repaglinide, valproic acid, verapamil

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CYP2C19 or CYP3A4 Inducers
Clinical Impact:	Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention:	St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions (5.9)]. Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:	Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
Intervention:	Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole.

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Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 5 Includes clinically significant drug interactions with BELBUCA.
Benzodiazepines
Clinical Impact:	There have been a number of reports regarding coma and death associated with the misuse and abuse of the combination of buprenorphine and benzodiazepines. In many, but not all of these cases, buprenorphine was misused by self-injection of crushed buprenorphine tablets. Preclinical studies have shown that the combination of benzodiazepines and buprenorphine altered the usual ceiling effect on buprenorphine-induced respiratory depression, making the respiratory effects of buprenorphine appear similar to those of full opioid agonists.
Intervention:	Closely monitor patients with concurrent use of BELBUCA and benzodiazepines. Warn patients that it is extremely dangerous to self-administer benzodiazepines while taking BELBUCA, and warn patients to use benzodiazepines concurrently with BELBUCA only as directed by their physician.
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, and other opioids, alcohol.
Inhibitors of CYP3A4
Clinical Impact:	The concomitant use of buprenorphine and CYP3A4 inhibitors can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of BELBUCA is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the buprenorphine plasma concentration will decrease [see Clinical Pharmacology (12.3)], potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to buprenorphine.
Intervention:	If concomitant use is necessary, consider dosage reduction of BELBUCA until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the BELBUCA dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples:	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact:	The concomitant use of buprenorphine and CYP3A4 inducers can decrease the plasma concentration of buprenorphine [see Clinical Pharmacology (12.3)], potentially resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to buprenorphine. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the buprenorphine plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both therapeutic effects and adverse reactions and may cause serious respiratory depression.
Intervention:	If concomitant use is necessary, consider increasing the BELBUCA dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider BELBUCA dosage reduction and monitor for signs of respiratory depression.
Examples:	Rifampin, carbamazepine, phenytoin
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue BELBUCA if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
Intervention:	The use of BELBUCA is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of BELBUCA and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine
Muscle Relaxants
Clinical Impact:	Buprenorphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients receiving muscle relaxants and BELBUCA for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of BELBUCA and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when BELBUCA is used concomitantly with anticholinergic drugs.
Antiretrovirals: Nucleoside reverse transcriptase inhibitors (NRTIs)
Clinical Impact:	Nucleoside reverse transcriptase inhibitors (NRTIs) do not appear to induce or inhibit the P450 enzyme pathway, thus no interactions with buprenorphine are expected.
Intervention:	None
Antiretrovirals: Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Clinical Impact:	Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are metabolized principally by CYP3A4. Efavirenz, nevirapine, and etravirine are known CYP3A inducers, whereas delaviridine is a CYP3A inhibitor. Significant pharmacokinetic interactions between NNRTIs (e.g., efavirenz and delavirdine) and buprenorphine have been shown in clinical studies, but these pharmacokinetic interactions did not result in any significant pharmacodynamic effects.
Intervention:	Patients who are on chronic BELBUCA treatment should have their dose monitored if NNRTIs are added to their treatment regimen.
Examples:	efavirenz, nevirapine, etravirine, delavirdine
Antiretrovirals: Protease inhibitors (PIs)
Clinical Impact:	Studies have shown some antiretroviral protease inhibitors (PIs) with CYP3A4 inhibitory activity (nelfinavir, lopinavir/ritonavir, ritonavir) have little effect on buprenorphine pharmacokinetic and no significant pharmacodynamic effects. Other PIs with CYP3A4 inhibitory activity (atazanavir and atazanavir/ritonavir) resulted in elevated levels of buprenorphine and norbuprenorphine, and patients in one study reported increased sedation. Symptoms of opioid excess have been found in post-marketing reports of patients receiving buprenorphine and atazanavir with and without ritonavir concomitantly.
Intervention:	Monitor patients taking BELBUCA and atazanavir with and without ritonavir, and dose reduction of BELBUCA may be warranted.
Examples:	atazanavir, ritonavir

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Drugs That Interfere with Hemostasis
Clinical Impact:	• Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	• During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

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Table 8: Clinically Significant Drug Interactions with Clarithromycin
Drugs That Are Affected By Clarithromycin
Drug(s) with Pharmacokinetics Affected by Clarithromycin	Recommendation	Comments
Antiarrhythmics:
Disopyramide Quinidine Dofetilide Amiodarone Sotalol Procainamide	Not Recommended	Disopyramide, Quinidine: There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs [see Warnings and Precautions (5.3)] . Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine. There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.
Digoxin	Use With Caution	Digoxin: Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are co-administered, inhibition of Pgp by clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range.
Oral Anticoagulants:
Warfarin	Use With Caution	Oral anticoagulants: Spontaneous reports in the postmarketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously [see Warnings and Precautions (5.4)] .
Antiepileptics:
Carbamazepine	Use With Caution	Carbamazepine: Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered. Increased serum concentrations of carbamazepine were observed in clinical trials with clarithromycin. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with carbamazepine.
Antifungals:
Itraconazole	Use With Caution	Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly (see also Itraconazole under “Drugs That Affect Clarithromycin” in the table below). Clarithromycin may increase the plasma concentrations of itraconazole. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions.
Fluconazole	No Dose Adjustment	Fluconazole: [see Pharmacokinetics (12.3)]
Anti-Gout Agents:
Colchicine (in patients with renal or hepatic impairment)	Contraindicated	Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. The dose of colchicine should be reduced when co-administered with clarithromycin in patients with normal renal and hepatic function [see Contraindications (4.4) and Warnings and Precautions (5.4)] .
Colchicine (in patients with normal renal and hepatic function)	Use With Caution
Antipsychotics:
Pimozide	Contraindicated	Pimozide: [See Contraindications (4.2)]
Quetiapine		Quetiapine: Quetiapine is a substrate for CYP3A4, which is inhibited by clarithromycin. Co-administration with clarithromycin could result in increased quetiapine exposure and possible quetiapine related toxicities. There have been postmarketing reports of somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation during concomitant administration. Refer to quetiapine prescribing information for recommendations on dose reduction if co-administered with CYP3A4 inhibitors such as clarithromycin.
Antispasmodics:
Tolterodine (patients deficient in CYP2D6 activity)	Use With Caution	Tolterodine: The primary route of metabolism for tolterodine is via CYP2D6. However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when co-administered with clarithromycin.
Antivirals:
Atazanavir	Use With Caution	Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)] .
Saquinavir (in patients with decreased renal function)		Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction (see Saquinavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)] .
Ritonavir Etravirine		Ritonavir, Etravirine: (see Ritonavir and Etravirine under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)] .
Maraviroc		Maraviroc: Clarithromycin may result in increases in maraviroc exposures by inhibition of CYP3A metabolism. See Selzentry ^® prescribing information for dose recommendation when given with strong CYP3A inhibitors such as clarithromycin.
Boceprevir (in patients with normal renal function) Didanosine	No Dose Adjustment	Boceprevir: Both clarithromycin and boceprevir are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when co-administered. No dose adjustments are necessary for patients with normal renal function (see Victrelis ^® prescribing information).
Zidovudine		Zidovudine: Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Administration of clarithromycin and zidovudine should be separated by at least two hours [see Pharmacokinetics (12.3)] . The impact of co-administration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated.
Calcium Channel Blockers:
Verapamil	Use With Caution	Verapamil: Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, [see Warnings and Precautions (5.4)] .
Amlodipine Diltiazem		Amlodipine, Diltiazem: [See Warnings and Precautions (5.4)]
Nifedipine		Nifedipine: Nifedipine is a substrate for CYP3A. Clarithromycin and other macrolides are known to inhibit CYP3A. There is potential of CYP3A-mediated interaction between nifedipine and clarithromycin. Hypotension and peripheral edema were observed when clarithromycin was taken concomitantly with nifedipine [see Warnings and Precautions (5.4)] .
Ergot Alkaloids:
Ergotamine Dihydroergotamine	Contraindicated	Ergotamine, Dihydroergotamine: Postmarketing reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4.6)] .
Gastroprokinetic Agents:
Cisapride	Contraindicated	Cisapride: [See Contraindications (4.2)]
HMG-CoA Reductase Inhibitors:
Lovastatin Simvastatin	Contraindicated	Lovastatin, Simvastatin, Atorvastatin, Pravastatin, Fluvastatin: [See Contraindications (4.5) and Warnings and Precautions (5.4)]
Atorvastatin Pravastatin	Use With Caution
Fluvastatin	No Dose Adjustment
Hypoglycemic Agents:
Nateglinide Pioglitazone Repaglinide Rosiglitazone	Use With Caution	Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]
Insulin		Insulin: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]
Immunosuppressants:
Cyclosporine	Use With Caution	Cyclosporine: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine.
Tacrolimus		Tacrolimus: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with tacrolimus.
Phosphodiesterase inhibitors:
Sildenafil Tadalafil Vardenafil	Use With Caution	Sildenafil, Tadalafil, Vardenafil: Each of these phosphodiesterase inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant administration of clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil, or vardenafil will result in increased exposure of these phosphodiesterase inhibitors. Co-administration of these phosphodiesterase inhibitors with clarithromycin is not recommended. Increased systemic exposure of these drugs may occur with clarithromycin; reduction of dosage for phosphodiesterase inhibitors should be considered (see their respective prescribing information).
Proton Pump Inhibitors:
Omeprazole	No Dose Adjustment	Omeprazole: The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when coadministered with clarithromycin as a result of increased omeprazole exposures [see Pharmacokinetics (12.3)] (see also Omeprazole under “Drugs That Affect Clarithromycin” in the table below).
Xanthine Derivatives:
Theophylline	Use With Caution	Theophylline: Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations [see Pharmacokinetics (12.3)] . Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range.
Triazolobenzodiazepines and Other Related Benzodiazepines:
Midazolam	Use With Caution	Midazolam: When oral midazolam is co-administered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated [see Warnings and Precautions (5.4) and Pharmacokinetics (12.3)] .
Alprazolam Triazolam		Triazolam, Alprazolam: Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is co-administered with clarithromycin. There have been postmarketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested. In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines.
Temazepam Nitrazepam Lorazepam	No Dose Adjustment	Temazepam, Nitrazepam, Lorazepam: For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.
Cytochrome P450 Inducers:
Rifabutin	Use With Caution	Rifabutin: Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis (see Rifabutin under “Drugs That Affect Clarithromycin” in the table below).
Other Drugs Metabolized by CYP3A:
Alfentanil Bromocriptine Cilostazol Methylprednisole Vinblastine Phenobarbital St. John’s Wort	Use With Caution	There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort.
Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A:
Hexobarbital Phenytoin Valproate	Use With Caution	There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.
Drugs that Affect Clarithromycin
Drug(s) that Affect the Pharmacokinetics of Clarithromycin	Recommendation	Comments
Antifungals:
Itraconazole	Use With Caution	Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions (see also Itraconazole under “Drugs That Are Affected By Clarithromycin” in the table above).
Antivirals:
Atazanavir	Use With Caution	Atazanavir: When clarithromycin is co-administered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology (12.3)] . Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.
Ritonavir (in patients with decreased renal function)		Ritonavir: Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with ritonavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium [see Pharmacokinetics (12.3)] . Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.
Saquinavir (in patients with decreased renal function)		Saquinavir: When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (refer to ritonavir above) [see Pharmacokinetics (12.3)] .
Etravirine		Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.
Saquinavir (in patients with normal renal function)	No Dose Adjustment
Ritonavir (in patients with normal renal function)
Proton Pump Inhibitors:
Omeprazole	Use With Caution	Omeprazole: Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole [see Pharmacokinetics (12.3)] .
Miscellaneous Cytochrome P450 Inducers:
Efavirenz Nevirapine Rifampicin Rifabutin Rifapentine	Use With Caution	Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are Affected By Clarithromycin” in the table above).

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.12, 7.3)

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Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Interacting Drug	Interaction
Antacids, sucralfate, multivitamins, and other products containing multivalent cations	Moxifloxacin absorption is decreased. Administer AVELOX Tablet at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3, 17.2)
Warfarin	Anticoagulant effect of warfarin may be enhanced. Monitor prothrombin time/INR, watch for bleeding. (6.4, 7.2, 12.3)
Class IA and Class III antiarrhythmics:	Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.3, 7.4)

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Classes of Drugs
Adrenal Cortical Steroid Inhibitors Antacids Antianxiety Agents Antiarrhythmics† Antibiotics† Anticonvulsants† Antidepressants† Antihistamines Antineoplastics†	Antipsychotic Medications Antithyroid Drugs† Barbiturates Diuretics† Enteral Nutritional Supplements Fungal Medications, Systemic† Gastric Acidity and Peptic Ulcer Agents† Hypnotics†	Hypolipidemics† Bile Acid-Binding Resins† HMG-CoA Reductase Inhibitors† Immunosuppressives Oral Contraceptives, Estrogen Containing Selective Estrogen Receptor Modulators Steroids, Adrenocortical† Tuberculosis Agents† Vitamins†

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Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
*Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	C _m _a _x
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing.
	20 mg/day	4 mg/day	1.6	-	Do not exceed 8 mg/day
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers)
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Table 2: Clinically Relevant Interactions Affecting Drugs Co-Administered with Rabeprazole Sodium Delayed-Release Tablets
Antiretrovirals
Clinical Impact :	The effect of PPI on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. • Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and nelfinavir) when used concomitantly with rabeprazole may reduce antiviral effect and promote the development of drug resistance. • Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with rabeprazole may increase toxicity. • There are other antiretroviral drugs which do not result in clinically relevant interactions with rabeprazole.
	Rilpivirine-containing products: Concomitant use with rabeprazole sodium delayed-release tablets are contraindicated [see CONTRAINDICATIONS (4)]. See prescribing information.
	Atazanavir : See prescribing information for atazanavir for dosing information.
Intervention :	Nelfinavir : Avoid concomitant use with rabeprazole sodium delayed-release tablets. See prescribing information for nelfinavir.
	Saquinavir : See the prescribing information for saquinavir and monitor for potential saquinavir toxicities.
	Other antiretrovirals : See prescribing information.
Warfarin
Clinical Impact :	Increased INR and prothrombin time in patients receiving PPIs, including rabeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death [see WARNINGS AND PRECAUTIONS (5.2)].
Intervention :	Monitor INR and prothrombin time. Dose adjustment of warfarin may be needed to maintain target INR range. See prescribing information for warfarin.
Methotrexate
Clinical Impact :	Concomitant use of rabeprazole with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of methotrexate with PPIs have been conducted [see WARNINGS AND PRECAUTIONS (5.9)].
Intervention :	A temporary withdrawal of rabeprazole sodium delayed-release tablets may be considered in some patients receiving high dose methotrexate administration.
Digoxin
Clinical Impact :	Potential for increased exposure of digoxin [see CLINICAL PHARMACOLOGY (12.3)].
Intervention :	Monitor digoxin concentrations. Dose adjustment of digoxin may be needed to maintain therapeutic drug concentrations. See prescribing information for digoxin.
Drugs Dependent on Gastric pH for Absorption ( e . g ., iron salts , erlotinib , dasatinib , nilotinib , mycophenolate mofetil , ketoconazole , itraconazole )
Clinical Impact :	Rabeprazole can reduce the absorption of drugs due to its effect on reducing intragastric acidity.
Intervention :	Mycophenolate mofetil (MMF): Co-administration of PPIs in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving PPIs and MMF. Use rabeprazole sodium delayed-release tablets with caution in transplant patients receiving MMF. See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact :	Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention :	See CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS in prescribing information for clarithromycin. See DRUG INTERACTIONS in prescribing information for amoxicillin.

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Table 1. Selected Drugs That Have Been Shown To or Are Predicted To Have Their Plasma Concentrations Altered By KetoconazoleThis list is not all-inclusive.
Systemic exposure to these drugs is increased significantly by the addition of ketoconazole: Concomitant use with ketoconazole is contraindicated.
Alprazolam, midazolam, triazolam	HMG-CoA reductase inhibitors (lovastatin, simvastatin)
Cisapride	Nisoldipine
Dofetilide	Pimozide
Eplerenone	Quinidine
Ergot alkaloids (ergotamine, dihydroergotamine)

Systemic exposure to these drugs is increased by ketoconazole: Careful monitoring, with possible adjustment in dosage, is recommended.
Alfentanil, fentanyl, sulfentanil	Indinavir, saquinavir
Amlodipine, felodipine, nicardipine, nifedipine	Methylprednisolone
Bosentan	Rifabutin
Buspirone	Sildenafil
Busulfan	Sirolimus (co-administration not recommended)
Carbamazepine	Tacrolimus
Cilostazol	Telithromycin
Cyclosporine	Tolterodine
Digoxin	Trimetrexate
Docetaxel, paclitaxel	Verapamil
Oral anti-coagulants	Vinca alkaloids (vincristine, - vinblastine, vinorelbine)

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Table 2: Drug Interactions: Pharmacokinetic Parameters for Indinavir in the Presence of the Coadministered Drug (See PRECAUTIONS, Table 9 for Recommended Alterations in Dose or Regimen)
Coadministered drug	Dose of Coadministered drug (mg)	Dose of CRIXIVAN (mg)	n	Ratio (with/without coadministered drug) of Indinavir Pharmacokinetic Parameters (90% CI); No Effect = 1.00
				C_max	AUC	C_min
All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
Cimetidine	600 twice daily, 6 days	400 single dose	12	1.07 (0.77, 1.49)	0.98 (0.81, 1.19)	0.82 (0.69, 0.99)
Clarithromycin	500 q12h, 7 days	800 three times daily, 7 days	10	1.08 (0.85, 1.38)	1.19 (1.00, 1.42)	1.57 (1.16, 2.12)
Delavirdine	400 three times daily	400 three times daily, 7 days	28	0.64Relative to indinavir 800 mg three times daily alone. (0.48, 0.86)	No significant change	2.18 (1.16, 4.12)
Delavirdine	400 three times daily	600 three times daily, 7 days	28	No significant change	1.53 (1.07, 2.20)	3.98 (2.04, 7.78)
EfavirenzStudy conducted in HIV-positive subjects.	600 once daily, 10 days	1000 three times daily, 10 days	20
		After morning dose		No significant change	0.67 (0.61, 0.74)	0.61 (0.49, 0.76)
		After afternoon dose		No significant change	0.63 (0.54, 0.74)	0.48 (0.43, 0.53)
		After evening dose		0.71 (0.57, 0.89)	0.54 (0.46, 0.63)	0.43 (0.37, 0.50)
Fluconazole	400 once daily, 8 days	1000 three times daily, 7 days	11	0.87 (0.72, 1.05)	0.76 (0.59, 0.98)	0.90 (0.72, 1.12)
Grapefruit Juice	8 oz.	400 single dose	10	0.65 (0.53, 0.79)	0.73 (0.60, 0.87)	0.90 (0.71, 1.15)
Isoniazid	300 once daily in the morning, 8 days	800 three times daily, 7 days	11	0.95 (0.88, 1.03)	0.99 (0.87, 1.13)	0.89 (0.75, 1.06)
Itraconazole	200 twice daily, 7 days	600 three times daily, 7 days	12	0.78 (0.69, 0.88)	0.99 (0.91, 1.06)	1.49 (1.28, 1.74)
Ketoconazole	400 once daily, 7 days	600 three times daily, 7 days	12	0.69 (0.61, 0.78)	0.80 (0.74, 0.87)	1.29 (1.11, 1.51)
	400 once daily, 7 days	400 three times daily, 7 days	12	0.42 (0.37, 0.47)	0.44 (0.41, 0.48)	0.73 (0.62, 0.85)
Methadone	20-60 once daily in the morning, 8 days	800 three times daily, 8 days	10	See text below for discussion of interaction.
Quinidine	200 single dose	400 single dose	10	0.96 (0.79, 1.18)	1.07 (0.89, 1.28)	0.93 (0.73, 1.19)
Rifabutin	150 once daily in the morning, 10 days	800 three times daily, 10 days	14	0.80 (0.72, 0.89)	0.68 (0.60, 0.76)	0.60 (0.51, 0.72)
Rifabutin	300 once daily in the morning, 10 days	800 three times daily, 10 days	10	0.75 (0.61, 0.91)	0.66 (0.56, 0.77)	0.61 (0.50, 0.75)
Rifampin	600 once daily in the morning, 8 days	800 three times daily, 7 days	12	0.13 (0.08, 0.22)	0.08 (0.06, 0.11)	Not Done
Ritonavir	100 twice daily, 14 days	800 twice daily, 14 days	10, 16Comparison to historical data on 16 subjects receiving indinavir alone.	See text below for discussion of interaction.
Ritonavir	200 twice daily, 14 days	800 twice daily,14 days	9, 16	See text below for discussion of interaction.
Sildenafil	25 single dose	800 three times daily	6	See text below for discussion of interaction.
St. John's wort (Hypericum perforatum, standardized to 0.3 % hypericin)	300 three times daily with meals, 14 days	800 three times daily	8	Not Available	0.46 (0.34, 0.58)95% CI.	0.19 (0.06, 0.33)
Stavudine (d4T)	40 twice daily, 7 days	800 three times daily, 7 days	11	0.95 (0.80, 1.11)	0.95 (0.80, 1.12)	1.13 (0.83, 1.53)
Trimethoprim/ Sulfamethoxazole	800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days	400 four times daily, 7 days	12	1.12 (0.87, 1.46)	0.98 (0.81, 1.18)	0.83 (0.72, 0.95)
Zidovudine	200 three times daily, 7 days	1000 three times daily, 7 days	12	1.06 (0.91, 1.25)	1.05 (0.86, 1.28)	1.02 (0.77, 1.35)
Zidovudine/ Lamivudine (3TC)	200/150 three times daily, 7 days	800 three times daily, 7 days	6, 9Parallel group design; n for indinavir + coadministered drug, n for indinavir alone.	1.05 (0.83, 1.33)	1.04 (0.67, 1.61)	0.98 (0.56, 1.73)

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Table 7:Effect of Other Drugs on Voriconazole Pharmacokinetics [ see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (Cmax and AUC after 200 mg q12h)	Recommendations for Voriconazole Dosage Adjustment/Comments
* Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects * Non-Nucleoside Reverse Transcriptase Inhibitors
Rifampin* and Rifabutin* (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (400 mg q24h)** (CYP450 Induction)	Significantly Reduced	Contraindicated

Efavirenz (300 mg q24h)** (CYP450 Induction)	Slight Decrease in AUCτ	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)** (CYP450 Induction)	Significantly Reduced	Contraindicated

Low-dose Ritonavir (100 mg q12h)** (CYP450 Induction)	Reduced	Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Phenytoin* (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. Johns Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives** containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole** (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir

	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIs*** (CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to voriconazole

	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Careful assessment of voriconazole effectiveness

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Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.7)].
Benzodiazepines (e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.7)]	Monitor sedation and blood pressure. Adjust dose accordingly.

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Table 3Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2) ].
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate. [See Warnings and Precautions (5.9) .]
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.11) and Use in Specific Populations (8.5) ].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [See Adverse Reactions (6.1) .]
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions (5.16) ].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies in and postmarketing.
Sildenafil	Use with caution Two-fold increase in exposure	Monitor for sildenafil toxicity (see Clinical Pharmacology (12.3 )].
Duloxetine	Avoid Use Five-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx^®(didanosine) chewable/ buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2.4)] .	Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

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albuterol, systemic and inhaled	diltiazem	medroxyprogesterone	roxithromycin
	dirithromycin	methylprednisolone	sorbitol(purgative doses
amoxicillin	enflurane	metronidazole	do not inhibit theophylline absorption)
ampicillin,with or without sulbactam	famotidine	metoprolol
	felodipine	nadolol
	finasteride	nifedipine
atenolol	hydrocortisone	nizatidine	sucralfate
azithromycin	isoflurane	norfloxacin	terbutaline, systemic
caffeine,dietary ingestion	isoniazid	ofloxacin	terfenadine
	isradipine	omeprazole	tetracycline
cefaclor	influenza vaccine	prednisone	tocainide
		prednisolone
co-trimoxazole(trimethoprim and sulfamethoxazole)	ketoconazole	mebendazole	ranitidine
	lomefloxacin	rifabutin

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 9: Predicted Drug Interactions with VIDEX
Drug or Drug Class	Effect	Clinical Comment
↑ Indicates increase. ↓ Indicates decrease. ^a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of VIDEX is recommended [ see Warnings and Precautions (5.1) ]. ^b [ See Warnings and Precautions (5.6) .]
Drugs that may cause pancreatic toxicity	↑ risk of pancreatitis	Use only with extreme caution^a
Neurotoxic drugs	↑ risk of neuropathy	Use with caution^b
Antacids containing magnesium or aluminum	↑ side effects associated with antacid components	Use caution with VIDEX Pediatric Powder for Oral Solution
Azole antifungals	↓ ketoconazole or itraconazole concentration	Administer drugs such as ketoconazole or itraconazole at least 2 hours before VIDEX.
Quinolone antibiotics (see also ciprofloxacin in Table 8)	↓ quinolone concentration	Consult package insert of the quinolone.
Tetracycline antibiotics	↓ antibiotic concentration	Consult package insert of the tetracycline.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 7.8, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 Inhibitors, (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with ezetimibe and simvastatin tablets
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg/10 mg ezetimibe and simvastatin tablets daily
Amiodarone, amlodipine, ranolazine	Do not exceed 10 mg/20 mg ezetimibe and simvastatin tablets daily
Lomitapide	For patients with HoFH, do not exceed 10 mg/20 mg ezetimibe and simvastatin tablets daily
Grapefruit juice	Avoid grapefruit juice

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Bleeding times
Clinical Impact:	Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention:	This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact:	The administration of naproxen may result in increased urinary values for 17 ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention:	Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact:	Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention:	This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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^aShould be administered at least 4 hours prior to WELCHOL
^bNo significant alteration of warfarin drug levels with warfarin and WELCHOL coadministration in an in vivo study which did not evaluate warfarin pharmacodynamics (INR). [See Post-marketing Experience (6.2)]
^c Cyclosporine levels should be monitored and, based on theoretical grounds, cyclosporine should be administered at least 4 hours prior to WELCHOL.
^dPatients receiving concomitant metformin ER and colesevelam should be monitored for clinical response as is usual for the use of anti-diabetes drugs.
Table 4 Drugs Tested in In Vitro Binding or In Vivo Drug Interaction Testing or With Post-Marketing Reports
Drugs with a known interaction with colesevelam: Decrease in exposure of coadministered drug	cyclosporine^c, glimepiride^a, glipizide^a, glyburide^a, levothyroxine^a, olmesartan medoxomil^a, and oral contraceptives containing ethinyl estradiol and norethindrone^a
Drugs with a known interaction with colesevelam: Increase in exposure of coadministered drug	metformin extended release (ER)^d
Drug(s) with postmarketing reports consistent with potential drug-drug interactions when coadministered with WELCHOL	phenytoin^a, warfarin^b
Drugs that do not interact with colesevelam based on in vitro or in vivo testing	aspirin, atenolol, cephalexin, ciprofloxacin, digoxin, enalapril, fenofibrate, lovastatin, metformin, metoprolol, phenytoin^a, pioglitazone, rosiglitazone, quinidine, repaglinide, sitagliptin, valproic acid, verapamil, warfarin^b

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TABLE 5: Summary of Effect of Coadministered Drugs on Exposure to Asenapine in Healthy Volunteers
Coadministered drug (Postulated effect on CYP450/UGT)	Dose schedules		Effect on asenapine pharmacokinetics		Recommendation
Coadministered drug (Postulated effect on CYP450/UGT)	Coadministered drug	Asenapine	C_max	AUC_0–∞
Fluvoxamine (CYP1A2 inhibitor)	25 mg twice daily for 8 days	5 mg Single Dose	+13%	+29%	Coadminister with cautionThe full therapeutic dose of fluvoxamine would be expected to cause a greater increase in asenapine plasma concentrations. AUC: Area under the curve.
Paroxetine (CYP2D6 inhibitor)	20 mg once daily for 9 days	5 mg Single Dose	–13%	–9%	No SAPHRIS dose adjustment required [see Drug Interactions (7.2)]
Imipramine (CYP1A2/2C19/3A4 inhibitor)	75 mg Single Dose	5 mg Single Dose	+17%	+10%	No SAPHRIS dose adjustment required
Cimetidine (CYP3A4/2D6/1A2 inhibitor)	800 mg twice daily for 8 days	5 mg Single Dose	–13%	+1%	No SAPHRIS dose adjustment required
Carbamazepine (CYP3A4 inducer)	400 mg twice daily for 15 days	5 mg Single Dose	–16%	–16%	No SAPHRIS dose adjustment required
Valproate (UGT1A4 inhibitor)	500 mg twice daily for 9 days	5 mg Single Dose	2%	–1%	No SAPHRIS dose adjustment required

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Summary of antiepileptic drug (AED) interactions with topiramate (7.1).
AED co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazaepine (CBZ)	NC	40% decrease
CBZ epoxideIs not administered but is an active metabolite of carbamazepine	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400mg/day	13% decrease

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion–the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide(including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide(including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄, and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5’-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.

Table name:

Interacting Drug	Interaction
Drugs known to prolong QT interval (e.g., Class IA and Class III antiarrhythmic agents).	Quinine sulfate capsules, USP prolongs QT interval, ECG abnormalities including QT prolongation and Torsades de Pointes. Avoid concomitant use ( 5.3).
Other antimalarials (e.g., halofantrine, mefloquine).	ECG abnormalities including QT prolongation. Avoid concomitant use ( 5.3, 7.2).
CYP3A4 inducers or inhibitors	Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine ( 7.1).
CYP3A4 and CYP2D6 substrates	Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the co-administered drug ( 7.2).
Digoxin	Increased digoxin plasma concentration ( 5.8, 7.1).

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Table 4: Clinically Important Drug Interactions with VIIBRYD
Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Monoamine Oxidase Inhibitors (MAOIs)	The concomitant use of MAOIs and serotonergic drugs including VIIBRYD increases the risk of serotonin syndrome.	VIIBRYD is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Contraindications (4), Dosage and Administration (2.3), and Warnings and Precautions (5.2)].
Other Serotonergic Drugs	The concomitant use of serotonergic drugs including VIIBRYD and other serotonergic drugs increases the risk of serotonin syndrome.	Monitor patients for signs and symptoms of serotonin syndrome, particularly during VIIBRYD initiation. If serotonin syndrome occurs, consider discontinuation of VIIBRYD and/or concomitant serotonergic drugs [see Warnings and Precautions (5.2)].
Antiplatelet Agents and Anticoagulants	Serotonin release by platelets plays an important role in hemostasis. The concurrent use of an antiplatelet agent or anticoagulant with VIIBRYD may potentiate the risk of bleeding.	Inform patients of the increased risk of bleeding with the concomitant use of VIIBRYD and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio (INR) when initiating or discontinuing VIIBRYD [see Warnings and Precautions (5.3)].
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin, voriconazole)	The concomitant use of VIIBRYD and strong CYP3A4 inhibitors increased the exposure of vilazodone compared to the use of VIIBRYD alone [see Clinical Pharmacology (12.3)].	The VIIBRYD dose should not exceed 20 mg once daily with the concomitant use of a strong CYP3A4 inhibitor [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].
Strong CYP3A4 Inducers (e.g., carbamazepine, phenytoin, rifampin)	The concomitant use of VIIBRYD and strong CYP3A4 inducers decreased the exposure of vilazodone compared to the use of VIIBRYD alone [see Clinical Pharmacology (12.3)].	Based on clinical response, consider increasing the dosage of VIIBRYD, over 1 to 2 weeks in patients taking strong CYP3A4 inducers for greater than 14 days [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].
Digoxin	Digoxin is a narrow therapeutic index drug. Concomitant use of VIIBRYD increased digoxin concentrations [see Clinical Pharmacology (12.3)].	Measure serum digoxin concentrations before initiating concomitant use of VIIBRYD. Continue monitoring and reduce digoxin dose as necessary.

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^a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. ^b = Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. NE = Not Evaluated
AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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LABORATORY TESTS	EFFECT OF SALICYLATES
Thyroid Function	Decreased PBI; increased T₃ uptake.
Urinary Sugar	False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5g q.d.).
5-Hydroxyindole acetic acid	False negative with fluorometric test.
Acetone, ketone bodies	False positive FeCl₃ in Gerhardt reaction; red color persists with boiling.
17-OH corticosteroids	False reduced values with >4.8g q.d. salicylate.
Vanilmandelic acid	False reduced values.
Uric acid	May increase or decrease depending on dose.
Prothrombin	Decreased levels; slightly increased prothrombin time.

Table name: Drugs That Are Affected By ClarithromycinDrug(s) with Pharmacokinetics Affected by ClarithromycinRecommendationComments Antiarrhythmics Disopyramide Quinidine Dofetilide Amiodarone Sotalol ProcainamideNot Recommended Disopyramide, Quinidine: There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs [see Warnings and Precautions ( 5.3 )]. Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine. There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.DigoxinUse With Caution Digoxin: Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are co‑ administered, inhibition of Pgp by clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing surveillance. Somepatients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range. Oral Anticoagulants WarfarinUse With CautionOral anticoagulants: Spontaneous reports in the postmarketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously [see Warnings and Precautions ( 5.4 )]. Antiepileptics CarbamazepineUse With Caution Carbamazepine: Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered. Increased serum concentrations of carbamazepine were observed in clinical trials with clarithromycin. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with carbamazepine. Antifungals ItraconazoleUse With CautionItraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly (see also Itraconazole under “Drugs That Affect Clarithromycin” in the table below). Clarithromycin may increase the plasma concentrations of itraconazole. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions.FluconazoleNo Dose Adjustment Fluconazole: [see Pharmacokinetics ( 12.3 )] Anti-Gout Agents Colchicine (in patients with renal or hepatic impairment)Contraindicated Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. Colchicine (in patients with normal renal and hepatic function)Use With CautionThe dose of colchicine should be reduced when co-administered with clarithromycin in patients with normal renal and hepatic function [see Contraindications ( 4.4 ) and Warnings and Precautions ( 5.4 )].Pimozide QuetiapineContraindicated Pimozide: [see Contraindications ( 4.2 )] Quetiapine: Quetiapine is a substrate for CYP3A4, which is inhibited by clarithromycin. Co‑ administration with clarithromycin could result in increased quetiapine exposure and possible quetiapine related toxicities. There have been postmarketing reports of somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation during concomitant administration. Refer to quetiapine prescribing information for recommendations on dose reduction if co‑ administered with CYP3A4 inhibitors such as clarithromycin. Antispasmodics : Tolterodine (patients deficient in CYP2D6 activity)Use With Caution Tolterodine: The primary route of metabolism for tolterodine is via CYP2D6. However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when co-administered with clarithromycin. Antivirals AtazanavirUse With Caution Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect” in the table below) [see Pharmacokinetics ( 12.3 )].Saquinavir (in patients with decreased renal function) Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction (see Saquinavir under “Drugs That Affect” in the table below) [see Pharmacokinetics ( 12.3 )].Ritonavir, Etravirine Ritonavir, Etravirine: (see Ritonavir and Etravirine under “Drugs That Affect” in the table below) [see Pharmacokinetics ( 12.3 )].Maraviroc Maraviroc: Clarithromycin may result in increases in maraviroc exposures by inhibition of CYP3A metabolism. See Selzentry® prescribing information for dose recommendation when given with strong CYP3A inhibitors such as clarithromycin.Boceprevir (in patients with normal renal function)No Dose AdjustmentBoceprevir: Both clarithromycin and boceprevir are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when co‑ administered. No dose adjustments are necessary for patients with normal renal function (see Victrelis® prescribing information).ZidovudineZidovudine: Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Administration of clarithromycin and zidovudine should be separated by at least two hours [see Pharmacokinetics ( 12.3 )]. The impact of co-administration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated. Calcium Channel Blockers VerapamilUse With Caution Verapamil: Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil [see Warnings and Precautions ( 5.4 )].Amlodipine, DiltiazemAmlodipine, Diltiazem: [See Warnings and Precautions ( 5.4 )]Nifedipine Nifedipine: Nifedipine is a substrate for CYP3A. Clarithromycin and other macrolides are known to inhibit CYP3A. There is potential of CYP3A‑ mediated interaction between nifedipine and clarithromycin. Hypotension and peripheral edema were observed when clarithromycin was taken concomitantly with nifedipine [see Warnings and Precautions ( 5.4 )]. Ergot Alkaloids Ergotamine DihydroergotamineContraindicated Ergotamine, Dihydroergotamine: Postmarketing reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications ( 4.6 )]. Gastroprokinetic Agents Cisapride HMG-CoA Reductase Inhibitor Lovastatin SimvastatinContraindicatedLovastatin, Simvastatin, Atorvastatin, Pravastatin,Fluvastatin: [See Contraindications ( 4.5 ) and Warnings and Precautions ( 5.4 )]Atorvastatin PravastatinUse With CautionFluvastatinNo Dose Adjustment Hypoglycemic Agents Nateglinide Pioglitazone Repaglinide RosiglitazoneUse With Caution Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone: [see Warnings and Precautions ( 5.4 ) and Adverse Reactions ( 6.2)]Insulin Insulin: [see Warnings and Precautions ( 5.4 ) and Adverse Reactions ( 6.2 )] Immunosuppressants CyclosporineUse With Caution Cyclosporine: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine.Tacrolimus Tacrolimus: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with tacrolimus. Phosphodiesterase inhibitors Sildenafil Tadalafil VardenafilUse With Caution Sildenafil, Tadalafil, Vardenafil: Each of these phosphodiesterase inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant administration of clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil, or vardenafil will result in increased exposure of these phosphodiesterase inhibitors. Co-administration of these phosphodiesterase inhibitors with clarithromycin is not recommended. Increased systemic exposure of these drugs may occur with clarithromycin; reduction of dosage for phosphodiesterase inhibitors should be considered (see their respective prescribing information). Proton Pump Inhibitors OmeprazoleNo Dose AdjustmentOmeprazole: The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when coadministered with clarithromycin as a result of increased omeprazole exposures [seePharmacokinetics ( 12.3 )](see also Omeprazole under “Drugs That Affect” in the table below). Xanthine Derivatives TheophyllineUse With Caution Theophylline: Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations [see Pharmacokinetics ( 12.3 )]. Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range. Triazolobenzodiazepines and Other Related Benzodiazepines MidazolamUse With Caution Midazolam: When oral midazolam is co‑ administered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated [see Warnings and Precautions ( 5.4 ) and Pharmacokinetics ( 12.3 )].Alprazolam Triazolam Triazolam, Alprazolam: Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is co-administered with clarithromycin. There have been postmarketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested. In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines.Temazepam Nitrazepam LorazepamNo Dose Adjustment Temazepam, Nitrazepam, Lorazepam: For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely. Cytochrome P450 Inducers RifabutinUse With Caution Rifabutin: Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis (see Rifabutin under “Drugs That Affect” in the table below). Other Drugs Metabolized by CYP3A Alfentanil Bromocriptine Cilostazol Vinblastine Methylprednisole Phenobarbital St. John’s WortUse With CautionThere have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort. Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A Hexobarbital Phenytoin ValproateUse With CautionThere have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproateDrugs that Affect ClarithromycinDrug(s) that Affect the Pharmacokinetics of ClarithromycinRecommendationComments Antifungals ItraconazoleUse With Caution Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions (see also Itraconazole under “Drugs That Are Affected By clarithromycin” in the table above). Antivirals AtazanavirUse With Caution Atazanavir: When clarithromycin is co-administered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology( 12.3 )]. Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co‑ administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.Ritonavir (in patients with decreased renal function) Ritonavir: Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with ritonavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium [see Pharmacokinetics ( 12.3 )]. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.Saquinavir (in patients with decreased renal function) Saquinavir: When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (refer to ritonavir above) [see Pharmacokinetics ( 12.3 )].Etravirine Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.Saquinavir (in patients with normal renal function) Ritonavir (in patients with normal renal function)No Dose Adjustment Proton Pump Inhibitors OmeprazoleUse With Caution Omeprazole: Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole [seePharmacokinetics ( 12.3 )] Miscellaneous Cytochrome P450 Inducers Efavirenz Nevirapine Rifampicin Rifabutin RifapentineUse With CautionInducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are Affected By clarithromycin” in the table above).




































Antipsychotics







































Contraindicated	Cisapride: [see Contraindications ( 4.2 )]

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. Do not coadminister the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

Table name:

Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

Table name:

Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol, systemic and inhaled	medroxyprogesterone
amoxicillin	methylprednisolone
ampicillin, with or without sulbactam	metronidazole
atenolol	metoprolol
azithromycin	nadolol
caffeine, dietary ingestion	nifedipine
cefaclor	nizatidine
co-trimoxazole	norfloxacin
(trimethoprim and sulfamethoxazole)	ofloxacin
diltiazem	omeprazole
dirithromycin	prednisone, prednisolone
enflurane	ranitidine
famotidine	rifabutin
felodipine	roxithromycin
finasteride	sorbitol
hydrocortisone	(purgative doses do not inhibit
isoflurane	theophylline absorption)
isoniazid	sucralfate
isradipine	terbutaline, systemic
influenza vaccine	terfenadine
ketoconazole	tetracycline
lomefloxacin	tocainide
mebendazole

Table name:

Table 2: Drug Interactions: Pharmacokinetic Parameters for Indinavir in the Presence of the Coadministered Drug (See PRECAUTIONS, Table 9 for Recommended Alterations in Dose or Regimen)
Coadministered drug	Dose of Coadministered drug (mg)	Dose of CRIXIVAN (mg)	n	Ratio (with/without coadministered drug) of Indinavir Pharmacokinetic Parameters (90% CI); No Effect = 1.00
				C_max	AUC	C_min
All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
Cimetidine	600 twice daily, 6 days	400 single dose	12	1.07 (0.77, 1.49)	0.98 (0.81, 1.19)	0.82 (0.69, 0.99)
Clarithromycin	500 q12h, 7 days	800 three times daily, 7 days	10	1.08 (0.85, 1.38)	1.19 (1.00, 1.42)	1.57 (1.16, 2.12)
Delavirdine	400 three times daily	400 three times daily, 7 days	28	0.64Relative to indinavir 800 mg three times daily alone. (0.48, 0.86)	No significant change	2.18 (1.16, 4.12)
Delavirdine	400 three times daily	600 three times daily, 7 days	28	No significant change	1.53 (1.07, 2.20)	3.98 (2.04, 7.78)
EfavirenzStudy conducted in HIV-positive subjects.	600 once daily, 10 days	1000 three times daily, 10 days	20
		After morning dose		No significant change	0.67 (0.61, 0.74)	0.61 (0.49, 0.76)
		After afternoon dose		No significant change	0.63 (0.54, 0.74)	0.48 (0.43, 0.53)
		After evening dose		0.71 (0.57, 0.89)	0.54 (0.46, 0.63)	0.43 (0.37, 0.50)
Fluconazole	400 once daily, 8 days	1000 three times daily, 7 days	11	0.87 (0.72, 1.05)	0.76 (0.59, 0.98)	0.90 (0.72, 1.12)
Grapefruit Juice	8 oz.	400 single dose	10	0.65 (0.53, 0.79)	0.73 (0.60, 0.87)	0.90 (0.71, 1.15)
Isoniazid	300 once daily in the morning, 8 days	800 three times daily, 7 days	11	0.95 (0.88, 1.03)	0.99 (0.87, 1.13)	0.89 (0.75, 1.06)
Itraconazole	200 twice daily, 7 days	600 three times daily, 7 days	12	0.78 (0.69, 0.88)	0.99 (0.91, 1.06)	1.49 (1.28, 1.74)
Ketoconazole	400 once daily, 7 days	600 three times daily, 7 days	12	0.69 (0.61, 0.78)	0.80 (0.74, 0.87)	1.29 (1.11, 1.51)
	400 once daily, 7 days	400 three times daily, 7 days	12	0.42 (0.37, 0.47)	0.44 (0.41, 0.48)	0.73 (0.62, 0.85)
Methadone	20-60 once daily in the morning, 8 days	800 three times daily, 8 days	10	See text below for discussion of interaction.
Quinidine	200 single dose	400 single dose	10	0.96 (0.79, 1.18)	1.07 (0.89, 1.28)	0.93 (0.73, 1.19)
Rifabutin	150 once daily in the morning, 10 days	800 three times daily, 10 days	14	0.80 (0.72, 0.89)	0.68 (0.60, 0.76)	0.60 (0.51, 0.72)
Rifabutin	300 once daily in the morning, 10 days	800 three times daily, 10 days	10	0.75 (0.61, 0.91)	0.66 (0.56, 0.77)	0.61 (0.50, 0.75)
Rifampin	600 once daily in the morning, 8 days	800 three times daily, 7 days	12	0.13 (0.08, 0.22)	0.08 (0.06, 0.11)	Not Done
Ritonavir	100 twice daily, 14 days	800 twice daily, 14 days	10, 16Comparison to historical data on 16 subjects receiving indinavir alone.	See text below for discussion of interaction.
Ritonavir	200 twice daily, 14 days	800 twice daily,14 days	9, 16	See text below for discussion of interaction.
Sildenafil	25 single dose	800 three times daily	6	See text below for discussion of interaction.
St. John's wort (Hypericum perforatum, standardized to 0.3 % hypericin)	300 three times daily with meals, 14 days	800 three times daily	8	Not Available	0.46 (0.34, 0.58)95% CI.	0.19 (0.06, 0.33)
Stavudine (d4T)	40 twice daily, 7 days	800 three times daily, 7 days	11	0.95 (0.80, 1.11)	0.95 (0.80, 1.12)	1.13 (0.83, 1.53)
Trimethoprim/ Sulfamethoxazole	800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days	400 four times daily, 7 days	12	1.12 (0.87, 1.46)	0.98 (0.81, 1.18)	0.83 (0.72, 0.95)
Zidovudine	200 three times daily, 7 days	1000 three times daily, 7 days	12	1.06 (0.91, 1.25)	1.05 (0.86, 1.28)	1.02 (0.77, 1.35)
Zidovudine/ Lamivudine (3TC)	200/150 three times daily, 7 days	800 three times daily, 7 days	6, 9Parallel group design; n for indinavir + coadministered drug, n for indinavir alone.	1.05 (0.83, 1.33)	1.04 (0.67, 1.61)	0.98 (0.56, 1.73)

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

Table name:

Factors	Dosage Adjustments for Aripiprazole Tablets
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors	Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double usual dose over 1 to 2 weeks

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

Table name:

Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [ see Contraindications (4.2) ] .
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [ s ee Warnings and Precautions (5.9) ] .
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.11) and Use in Specific Populations (8.5) ].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were coadministered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is coadministered with oral antidiabetic drugs [ s ee Adverse Reactions (6.1) ] .
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is coadministered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after coadministration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.16) ].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after coadministration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution Two-fold increase in exposure	Monitor for sildenafil toxicity [ s ee C li n ic a l Pha r m a c o l og y ( 1 2 .3)].
Duloxetine	Avoid Use Five-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx^® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2.4) ].	Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

Table name:

Figure 7: Mean Standing Systolic Blood Pressure Change from Baseline

Table name:

Drug	Description
Corticosteroids	Decreases plasma salicylate level; Tapering doses of steroids may promote salicylism
Ammonium Sulfate	Increases plasma salicylate level

Table name:

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

Table 3: Clinically Relevant Interactions Affecting Drugs Co-Administered with Omeprazole and Interaction with Diagnostics
Antiretrovirals
Clinical Impact:	The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
Intervention:	Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications (4)]. Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:	Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention:	Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact:	Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].
Intervention:	A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact:	Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)]. There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention:	Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6)].
Citalopram
Clinical Impact:	Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention:	Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:	Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].
Intervention:	Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:	Potential for increased exposure of phenytoin.
Intervention:	Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:	Increased exposure of diazepam [see Clinical Pharmacology (12.3)].
Intervention:	Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:	Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention:	Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:	Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:	Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)]. See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:	Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:	See Contraindications, Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact:	Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention:	Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:	Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10), Clinical Pharmacology (12.2)].
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:	Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact:	There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:	An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:	There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:	Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.

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Table 3Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Summary of AED interactions with topiramate (7.1).
AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400mg/day	13% decrease

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Table 5: AED Drug Interactions with Oxcarbazepine
AED Coadministered (daily dose)	IR-Oxcarbazepine (daily dose)	Influence of IR-Oxcarbazepine on AED Concentration Mean Change [90% Confidence Interval]	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)	Recommendation
Carbamazepine (400 – 2000 mg)	900 mg	ncnc denotes a mean change of less than 10%	40% decrease [CI: 17% decrease, 57% decrease]	Consider initiating Oxtellar XR^® at a higher dose. Monitor and titrate dose to desired clinical effect (see 2.6)
Phenobarbital (100 – 150 mg)	600 – 1800 mg	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin (250 – 500 mg)	600 – 1800 >1200-2400	nc ^, Pediatrics up to 40% increaseMean increase in adults at high doses of immediate-release oxcarbazepine [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic Acid (400 – 2800 mg)	600-1800	nc	18% decrease [CI: 13% decrease, 40% decrease]	Monitor. Dose adjustment of Oxtellar XR^® may not be needed.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion–the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide(including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. ₄ ₃
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide(including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T , and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. ₄ ₄ ₄ ₄ ₃ ₄ ₄ ₄
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. ₄
Drugs that may decrease T ₄ 5’-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T to T , leading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T and T levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). ₄ ₃ ₃ ₄ ₃ ₄ ₃ ₄ ₃ ₄
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of I, I, and Tc. ¹²³ ¹³¹ ^99m
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.

Table name:

Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

Table name:

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 3: Clinically Significant drug interactions with Celecoxib
Drugs That Interfere with Hemostasis
Clinical Impact :	Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of Celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention :	Monitor patients with concomitant use of celecoxib capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact :	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200-400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100-325 mg).
Intervention :	Concomitant use of celecoxib capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Celecoxib capsules are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors , Angiotensin Receptor Blockers , and Beta - Blockers
Clinical Impact :	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention :	During concomitant use of celecoxib capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of celecoxib capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact :	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention :	During concomitant use of celecoxib capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Digoxin
Clinical Impact :	The concomitant use of Celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention :	During concomitant use of celecoxib capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact :	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention :	During concomitant use of celecoxib capsules and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact :	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Celecoxib has no effect on methotrexate pharmacokinetics.
Intervention :	During concomitant use of celecoxib capsules and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact :	Concomitant use of celecoxib capsules and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention :	During concomitant use of celecoxib capsules and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact :	Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention :	The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact :	Concomitant use of celecoxib capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention :	During concomitant use of celecoxib capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or inducers
Clinical Impact :	Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Coadministration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib.
Intervention :	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [see Clinical Pharmacology (12.3)].
CYP2D6 substrates
Clinical Impact :	In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs.
Intervention :	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [see Clinical Pharmacology (12.3)].
Corticosteroids
Clinical Impact :	Concomitant use of corticosteroids with celecoxib capsules may increase the risk of GI ulceration or bleeding.
Intervention :	Monitor patients with concomitant use of celecoxib capsules with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)].

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
*Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	C_m _a _x
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing.
	20 mg/day	4 mg/day	1.6	-	Do not exceed 8 mg/day
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers)
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

Table name: ContraindicatedAvoid UseUse with cautionUse with cautionUse with caution

Table 4: Drugs That are Affected by and Affecting CIPRO
Drugs That are Affected by CIPRO
Drug(s)	Recommendation		Comments
Tizanidine
Concomitant administration of tizanidine and CIPRO XR is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)		Concurrent administration of CIPRO XR with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.9)].
Drugs Known to Prolong QT Interval
Cipro XR may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.11) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated		Hypoglycemia sometimes severe has been reported when CIPRO XR and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when CIPRO XR is co-administered with oral antidiabetic drugs [see Adverse Reactions (6.1)].
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)		To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon CIPRO XR discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of CIPRO XR with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)		Monitor renal function (in particular serum creatinine) when CIPRO XR is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)		The risk may vary with the underlying infection, age and general status of the patient so that the contribution of CIPRO XR to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of CIPRO XR with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels		Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant CIPRO XR therapy is indicated.
Ropinirole
Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with CIPRO XR [see Warnings and Precautions (5.15)].
Clozapine
Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with CIPRO XR are advised.
NSAIDs
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution Two-fold increase in exposure		Monitor for sildenafil toxicity [see Clinical Pharmacology (12.3)]..
Duloxetine	Avoid Use Five-fold increase in duloxetine exposure		If unavoidable monitor, for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life		CIPRO XR inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of CIPRO XR
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx^® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)		CIPRO XR should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration ( 2)].	Decrease CIPRO XR absorption, resulting in lower serum and urine levels considerably lower than desired for concurrent administration of these agents with CIPRO XR
Probenecid		Use with caution (interferes with renal tubular secretion of CIPRO XR and increases CIPRO XR serum levels)	Potentiation of CIPRO XR toxicity may occur.

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Table 9: Drugs That are Affected by and Affecting Ciprofloxacin Tablets
Drugs That are Affected by C iprofloxacin Tablets
Drug(s)	Recommendation		Comments
Tizanidine	Contraindicated		Concomitant administration of tizanidine and ciprofloxacin tablets is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [ see Contraindications ( 4.2 )]
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)		Concurrent administration of ciprofloxacin tablets with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [s ee Warnings and Precautions ( 5.9 ) ] .
Drugs Known to Prolong QT Interval	Avoid Use		Ciprofloxacin tablets may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions ( 5.11 ) and Use in Specific Populations ( 8.5 )].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated		Hypoglycemia sometimes severe has been reported when ciprofloxacin tablets and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin tablets is co-administered with oral antidiabetic drugs [see Adverse Reactions ( 6.1)].
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)		To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin tablets discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin tablets with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)		Monitor renal function (in particular serum creatinine) when ciprofloxacin tablets is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)		The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin tablets to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin tablets with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels		Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin tablets therapy is indicated.
Ropinirole	Use with caution		Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin tablets [ see Warnings and Precautions ( 5.16 ) ] .
Clozapine	Use with caution		Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin tablets are advised.
NSAIDs	Use with caution		Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution Two-fold increase in exposure		Monitor for sildenafil toxicity [see clinical Pharmacology ( 12.3)].
Duloxetine	Avoid Use Five-fold increase in duloxetine exposure		If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life		Ciprofloxacin tablets inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin Tablets
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)		Ciprofloxacin tablets should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration ( 2.4 ) ] .		Decrease ciprofloxacin tablets absorption, resulting in lower serum and urine levels
Probenecid		Use with caution (interferes with renal tubular secretion of ciprofloxacin tablets and increases ciprofloxacin tablets serum levels)		Potentiation of ciprofloxacin tablets toxicity may occur.

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Table II. Clinically significant drug interactions with theophylline.
Drug	Type of Interaction	Effect
Adenosine	Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.
Alcohol	A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours.	30% increase
Allopurinol	Decreases theophylline clearance at allopurinol doses ≥600 mg/day.	25% increase
Aminoglutethimide	Increases theophylline clearance by induction of microsomal enzyme activity.	25% decrease
Carbamazepine	Similar to aminoglutethimide.	30% decrease
Cimetidine	Decreases theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase
Ciprofloxacin	Similar to cimetidine.	40% increase
Clarithromycin	Similar to erythromycin.	25% increase
Diazepam	Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.	Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram	Decreases theophylline clearance by inhibiting hydroxylation and demethylation.	50% increase
Enoxacin	Similar to cimetidine.	300% increase
Ephedrine	Synergistic CNS effects	Increased frequency of nausea, nervousness, and insomnia.
Erythromycin	Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen	Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.	30% increase
Flurazepam	Similar to diazepam.	Similar to diazepam.
Fluvoxamine	Similar to cimetidine.	Similar to cimetidine.
Halothane	Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.	Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A	Decreases theophylline clearance.	100% increase
Isoproterenol (IV)	Increase theophylline clearance.	20% increase
Ketamine	Pharmacologic	May lower theophylline seizure threshold.
Lithium	Theophylline increases renal lithium clearance.	Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam	Similar to diazepam.	Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.	20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine	Similar to disulfiram.	80% increase
Midazolam	Similar to diazepam.	Similar to diazepam.
Moricizine	Increases theophylline clearance.	25% decrease
Pancuronium	Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.	Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline	Decreases theophylline clearance.	30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.	25% decrease after two weeks of concurrent PB.
Phenytoin	Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.	Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone	Decreases theophylline clearance and pharmacologic interaction.	40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and pharmacologic interaction.	100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin	Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.	20 to 40% decrease
Sulfinpyrazone	Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.	20% increase
Tacrine	Similar to cimetidine, also increases renal clearance of theophylline.	90% increase
Thiabendazole	Decreases theophylline clearance.	190% increase
Ticlopidine	Decreases theophylline clearance.	60% increase
Troleandomycin	Similar to erythromycin.	33 to 100% increase depending on troleandomycin dose.
Verapamil	Similar to disulfiram.	20% increase

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Drugs that Affect Renal Function	A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics	Dofetilide	Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
	Sotalol	Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
	Dronedarone	Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog	Teriparatide	Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement	Thyroid	Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics	Epinephrine Norepinephrine Dopamine	Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents	Succinylcholine	May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements	Calcium	If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers		Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.
Hyperpolarization-activated cyclic nucleotide-gated channel blocker	Ivabradine	Can increase the risk of bradycardia

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Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Table 13. Established and Other Potentially Significant Drug Interactions
↓= Decreased (induces lamotrigine glucuronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
?= Conflicting data.
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Table 1: Clinically Significant Drug Interactions with Naproxen
Drugs That Interfere with Hemostasis
Clinical Impact:	Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of naproxen tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	Concomitant use of naproxen tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen tablets are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of naproxen tablets and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of naproxen tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention	During concomitant use of naproxen tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of naproxen tablets and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen tablets and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen tablets and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen tablets and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen tablets and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen tablets and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of naproxen tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen tablets are not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen tablets are not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxen tablets are not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen tablets and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:	Patients simultaneously receiving naproxen tablets and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

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Diuretics
Clinical Impact:	Diuretic-induced sodium loss may reduce lithium clearance and increase serum lithium concentrations.
Intervention:	More frequent monitoring of serum electrolyte and lithium concentrations. Reduce lithium dosage based on serum lithium concentration and clinical response [see Dosage and Administration (2.6), Warning and Precautions (5.3)].
Examples:	hydrochlorothiazide, chlorothiazide, furosemide
Non-Steroidal Anti-inflammatory Drugs (NSAID)
Clinical Impact:	NSAID decrease renal blood flow, resulting in decreased renal clearance and increased serum lithium concentrations.
Intervention:	More frequent serum lithium concentration monitoring. Reduce lithium dosage based on serum lithium concentration and clinical response [see Dosage and Administration (2.6)].
Examples:	indomethacin, ibuprofen, naproxen
Renin-Angiotensin System Antagonists
Clinical Impact:	Concomitant use increase steady-state serum lithium concentrations.
Intervention:	More frequent monitoring of serum lithium concentration. Reduce lithium dosage based on serum lithium concentration and clinical response [see Dosage and Administration (2.6)].
Examples:	lisinopril, enalapril, captopril, valsartan
Serotonergic Drugs
Clinical Impact:	Concomitant use can precipitate serotonin syndrome.
Intervention:	Monitor patients for signs and symptoms of serotonin syndrome, particularly during lithium initiation. If serotonin syndrome occurs, consider discontinuation of lithium and/or concomitant serotonergic drugs [see Warnings and Precautions (5.6)].
Examples:	selective serotonin reuptake inhibitors (SSRI), serotonin and norepinephrine reuptake inhibitors (SNRI), monoamine oxidase inhibitors (MAOI)
Nitroimidazole Antibiotics
Clinical Impact:	Concomitant use may cause lithium toxicity due to reduced renal clearance.
Intervention:	More frequent monitoring of serum lithium concentration. Reduce lithium dosage based on serum lithium concentration and clinical response [see Dosage and Administration (2.6)].
Examples:	metronidazole
Acetazolamide, Urea, Xanthine Preparations, Alkalinizing Agents
Clinical Impact:	Concomitant use can lower serum lithium concentrations by increasing urinary lithium excretion.
Intervention:	More frequent serum lithium concentration monitoring. Increase lithium dosage based on serum lithium concentration and clinical response [see Dosage and Administration (2.6)].
Examples:	acetazolamide, theophylline, sodium bicarbonate
Methyldopa, Phenytoin and Carbamazepine
Clinical Impact:	Concomitant use may increase risk of toxic effects of these drugs
Intervention:	Monitor patients closely for symptoms of toxicity of methyldopa, phenytoin, and carbamazepine.
Iodide Preparations
Clinical Impact:	Concomitant use may produce hypothyroidism.
Intervention:	Monitor patients for signs or symptoms of hypothyroidism [see Warnings and Precautions (5.7)].
Examples:	potassium iodide
Calcium Channel Blocking Agents (CCB)
Clinical Impact:	Concomitant use may increase the risk of neurologic adverse reactions in the form of ataxia, tremors, nausea, vomiting, diarrhea and/or tinnitus.
Intervention:	Monitor for neurologic adverse reactions.
Examples:	diltiazem, nifedipine, verapamil
Atypical and Typical Antipsychotic Drugs
Clinical Impact:	Reports of neurotoxic reactions in patients treated with both lithium and an antipsychotic, ranging from extrapyramidal symptoms to neuroleptic malignant syndrome, as well as reports of an encephalopathic syndrome in few patients treated with concomitant therapy [see Warnings and Precautions (5.5)].
Intervention:	Monitor for neurologic adverse reactions.
Examples:	risperidone, haloperidol, thioridazine, fluphenazine, chlorpromazine, perphenazine, clozapine
Neuromuscular Blocking Agents
Clinical Impact:	Lithium may prolong the effects of neuromuscular blocking agents.
Intervention:	Monitor for prolonged paralysis or toxicity.
Examples:	succinylcholine, pancuronium

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Table 2: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 5 mg in BPH patients on stable alpha-blocker therapy (Study 1)
Alpha-Blocker		Simultaneous dosing of Vardenafil 5 mg and Alpha-Blocker, Placebo-Subtracted	Dosing of Vardenafil 5 mg and Alpha-Blocker Separated by 6 Hours, Placebo-Subtracted
Terazosin 5 or 10 mg daily	Standing SBP	-3 (-6.7, 0.1)	-4 (-7.4, -0.5)
Terazosin 5 or 10 mg daily	Supine SBP	-4 (-6.7, -0.5)	-4 (-7.1, -0.7)
Tamsulosin 0.4 mg daily	Standing SBP Supine SBP	-6 (-9.9, -2.1) -4 (-7.0, -0.8)	-4 (-8.3, -0.5) -5 (-7.9, -1.7)

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 7.8, 12.3)
Interacting Agents	Prescribing
	Recommendations
Strong CYP3A4 Inhibitors, (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistatcontaining products), gemfibrozil, cyclosporine, danazol	Contraindicated with ezetimibe and simvastatin

Verapamil, diltiazem, dronedarone	Do not exceed 10 mg/10 mg ezetimibe and simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 10 mg/20 mg ezetimibe and simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 10 mg/20 mg ezetimibe and simvastatin daily*
Grapefruit juice	Avoid grapefruit juice
* For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 10 mg/40 mg ezetimibe and simvastatin when taking lomitapide.

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Table 7 Summary of AED Interactions with Oxcarbazepine
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean change, 90% Confidence Interval)
Carbamazepine	400 to 2000	900	ncnc denotes a mean change of less than 10%	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100 to 150	600 to 1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250 to 500	600 to 1800 >1200 to 2400	nc, Pediatrics up to 40% increaseMean increase in adults at high oxcarbazepine doses [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decease]
Valproic acid	400 to 2800	600 to 1800	nc	18% decrease [CI: 13% decrease, 40% decrease]

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Drugs That Interfere with Hemostasis
Clinical Impact:	• Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of naproxen delayed-release tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding ( see WARNINGS; Hematologic Toxicity ).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation) .
Intervention:	Concomitant use of naproxen delayed-release tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen delayed-release tablets are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	• During concomitant use of naproxen delayed-release tablets and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen delayed-release tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention	During concomitant use of naproxen delayed-release tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of naproxen delayed-release tablets and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance . The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen delayed-release tablets and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen delayed-release tablets and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen delayed-release tablets and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen delayed-release tablets and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen delayed-release tablets and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of naproxen delayed-release tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen delayed-release tablets is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed-release tablets is not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxen delayed-release tablets is not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen delayed-release tablets and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin .
Intervention:	Patients simultaneously receiving naproxen delayed-release tablets and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

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Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2) ].
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate. [See Warnings and Precautions (5.6) .]
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5) ].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [See Adverse Reactions (6.1) .]
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions (5.15) ].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies in and postmarketing.
Sildenafil	Use with caution Two-fold increase in exposure	Monitor for sildenafil toxicity (see Pharmacokinetics 12.3 ).
Duloxetine	Avoid Use Five-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx^®(didanosine) chewable/ buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2) ].	Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

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Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio Change relative to reference )		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	C_max
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 mg or 3 mg twice daily	1.4	1.5	Reevaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	--	Reevaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	--
	40 mg/day -	4 mg/day	1.8	--
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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DRUG	DESCRIPTION OF INTERACTION
Corticosteroids	Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents	Increases plasma salicylate level.
Alkanizing Agents	Decreased plasma salicylate levels.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Anti-diabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)	Do not exceed 40 mg atorvastatin daily

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Table 9: Drugs That are Affected by and Affecting Ciprofloxacin Tablets
Drugs That are Affected by C iprofloxacin Tablets
Drug(s)	Recommendation		Comments
Tizanidine	Contraindicated		Concomitant administration of tizanidine and ciprofloxacin tablets is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [ see Contraindications ( 4.2 )]
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)		Concurrent administration of ciprofloxacin tablets with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [s ee Warnings and Precautions ( 5.9 ) ] .
Drugs Known to Prolong QT Interval	Avoid Use		Ciprofloxacin tablets may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions ( 5.11 ) and Use in Specific Populations ( 8.5 )].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated		Hypoglycemia sometimes severe has been reported when ciprofloxacin tablets and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin tablets is co-administered with oral antidiabetic drugs [see Adverse Reactions ( 6.1)].
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)		To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin tablets discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin tablets with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)		Monitor renal function (in particular serum creatinine) when ciprofloxacin tablets is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)		The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin tablets to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin tablets with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels		Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin tablets therapy is indicated.
Ropinirole	Use with caution		Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin tablets [ see Warnings and Precautions ( 5.16 ) ] .
Clozapine	Use with caution		Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin tablets are advised.
NSAIDs	Use with caution		Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution Two-fold increase in exposure		Monitor for sildenafil toxicity [see clinical Pharmacology ( 12.3)].
Duloxetine	Avoid Use Five-fold increase in duloxetine exposure		If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life		Ciprofloxacin tablets inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin Tablets
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)		Ciprofloxacin tablets should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration ( 2.4 ) ] .		Decrease ciprofloxacin tablets absorption, resulting in lower serum and urine levels
Probenecid		Use with caution (interferes with renal tubular secretion of ciprofloxacin tablets and increases ciprofloxacin tablets serum levels)		Potentiation of ciprofloxacin tablets toxicity may occur.

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Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing.
	20 mg/day	4 mg/day	1.6	-	Do not exceed 8 mg/day
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed

Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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May Require a Decrease in Dose at Cessation of Smoking	Possible Mechanism
Acetaminophen, caffeine, imipramine, oxazepam, pentazocine, propranolol, or other beta-blockers, theophylline	Deinduction of hepatic enzymes on smoking cessation.
Insulin	Increase of subcutaneous insulin absorption with smoking cessation.
Adrenergic antagonists (e.g. prazosin, labetalol)	Decrease in circulating catecholamines with smoking cessation.
May Require an Increase in Dose at Cessation of Smoking	Possible Mechanism
Adrenergic agonists (e.g. isoproterenol, phenylephrine)	Decrease in circulating catecholamines with smoking cessation.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. ( 2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidibetic agents	Carefully monitor blood glucose ( 5.12, 7.3)

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Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs that Interfere with Hemostasis
Clinical Impact :	Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention :	Monitor patients with concomitant use of Meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact :	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention :	Concomitant use of Meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors , Angiotensin Receptor Blockers , or Beta - Blockers
Clinical Impact :	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention :	During concomitant use of Meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of Meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact :	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention :	During concomitant use of Meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Lithium
Clinical Impact :	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology (12.3)].
Intervention :	During concomitant use of Meloxicam and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact :	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention :	During concomitant use of Meloxicam and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact :	Concomitant use of Meloxicam and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention :	During concomitant use of Meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact :	Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention :	The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact :	Concomitant use of Meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention :	During concomitant use of Meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.

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Table 4: Clinically Important Drug Interactions with VIIBRYD
Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Monoamine Oxidase Inhibitors (MAOIs)	The concomitant use of MAOIs and serotonergic drugs including VIIBRYD increases the risk of serotonin syndrome.	VIIBRYD is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Contraindications (4), Dosage and Administration (2.3), and Warnings and Precautions (5.2)].
Other Serotonergic Drugs	The concomitant use of serotonergic drugs including VIIBRYD and other serotonergic drugs increases the risk of serotonin syndrome.	Monitor patients for signs and symptoms of serotonin syndrome, particularly during VIIBRYD initiation. If serotonin syndrome occurs, consider discontinuation of VIIBRYD and/or concomitant serotonergic drugs [see Warnings and Precautions (5.2)].
Antiplatelet Agents and Anticoagulants	Serotonin release by platelets plays an important role in hemostasis. The concurrent use of an antiplatelet agent or anticoagulant with VIIBRYD may potentiate the risk of bleeding.	Inform patients of the increased risk of bleeding with the concomitant use of VIIBRYD and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio (INR) when initiating or discontinuing VIIBRYD [see Warnings and Precautions (5.3)].
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin, voriconazole)	The concomitant use of VIIBRYD and strong CYP3A4 inhibitors increased the exposure of vilazodone compared to the use of VIIBRYD alone [see Clinical Pharmacology (12.3)].	The VIIBRYD dose should not exceed 20 mg once daily with the concomitant use of a strong CYP3A4 inhibitor [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].
Strong CYP3A4 Inducers (e.g., carbamazepine, phenytoin, rifampin)	The concomitant use of VIIBRYD and strong CYP3A4 inducers decreased the exposure of vilazodone compared to the use of VIIBRYD alone [see Clinical Pharmacology (12.3)].	Based on clinical response, consider increasing the dosage of VIIBRYD, over 1 to 2 weeks in patients taking strong CYP3A4 inducers for greater than 14 days [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].
Digoxin	Digoxin is a narrow therapeutic index drug. Concomitant use of VIIBRYD increased digoxin concentrations [see Clinical Pharmacology (12.3)].	Measure serum digoxin concentrations before initiating concomitant use of VIIBRYD. Continue monitoring and reduce digoxin dose as necessary.

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Interacting Drug	Interaction
Multivalent cation-containing products including: antacids, sucralfate, multivitamins	Decreased moxifloxacin absorption. Take moxifloxacin hydrochloride tablet at least 4 hours before or 8 hours after these products. (2.2, 7.1, 12.3)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time/INR, and bleeding. (6, 7.2, 12.3)
Class IA and Class III antiarrhythmics:	Proarrhythmic effect may be enhanced. Avoid concomitant use. (5.6, 7.5)
Antidiabetic agents	Carefully monitor blood glucose. (5.11, 7.3)

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NA – Not available/reported
Digoxin concentrations increased greater than 50%
	Digoxin Serum Concentration Increase	Digoxin AUC Increase	Recommendations
Amiodarone	70%	NA	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
Captopril	58%	39%
Clarithromycin	NA	70%
Dronedarone	NA	150%
Gentamicin	129-212%	NA
Erythromycin	100%	NA
Itraconazole	80%	NA
Lapatinib	NA	180%
Nitrendipine	57%	15%
Propafenone	NA	60-270%
Quinidine	100%	NA
Ranolazine	50%	NA
Ritonavir	NA	86%
Telaprevir	50%	85%
Tetracycline	100%	NA
Verapamil	50-75%	NA
Digoxin concentrations increased less than 50%
Atorvastatin	22%	15%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
Carvedilol	16%	14%
Conivaptan	33%	43%
Diltiazem	20%	NA
Indomethacin	40%	NA
Nefazodone	27%	15%
Nifedipine	45%	NA
Propantheline	24%	24%
Quinine	NA	33%
Rabeprazole	29%	19%
Saquinavir	27%	49%
Spironolactone	25%	NA
Telmisartan	20-49%	NA
Ticagrelor	31%	28%
Tolvaptan	30%	20%
Trimethoprim	22-28%	NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate, sulfasalazine			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20-40% as necessary.

Table name: Disopyramide Quinidine Dofetilide Amiodarone Sotalol Procainamide Digoxin Warfarin Carbamazepine Itraconazole Fluconazole Colchicine
(In Patients with Renal or Hepatic Impairment) Colchicine
(In Patients with Normal Renal and Hepatic Function) Pimozide Quetiapine Tolterodine
(Patients Deficient in CYP2D6 Activity) Atazanavir Saquinavir
(In Patients with
Decreased Renal Function) Ritonavir Etravirine Maraviroc Boceprevir
(In Patients with
Normal Renal Function) DidanosineZidovudine Verapamil Amlodipine Diltiazem Nifedipine Ergotamine Dihydroergotamine Cisapride Lovastatin Simvastatin Atorvastatin Pravastatin Fluvastatin Nateglinide Pioglitazone Repaglinide Rosiglitazone Insulin Cyclosporine Tacrolimus Sildenafil Tadalafil Vardenafil Omeprazole Theophylline Midazolam Alprazolam Triazolam Temazepam Nitrazepam Lorazepam Rifabutin Alfentanil Bromocriptine Cilostazol Methylprednisole Vinblastine Phenobarbital St. John’s Wort Hexobarbital Phenytoin Valproate Itraconazole Atazanavir Ritonavir (In Patients with
Decreased Renal Function) Saquinavir
(In Patients with
Decreased Renal Function) Etravirine Saquinavir
(In Patients with
Normal Renal Function) Ritonavir
(In Patients with
Normal Renal Function) Omeprazole Efavirenz Nevirapine Rifampicin Rifabutin Rifapentine

Table 8: Clinically Significant Drug Interactions with Clarithromycin
Drugs That Are Affected By Clarithromycin
Drug(s) with Pharmacokinetics Affected by Clarithromycin	Recommendation	Comments
Antiarrhythmics:

Not Recommended	Disopyramide, Quinidine: There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during co-administration of clarithromycin with these drugs [see Warnings and Precautions (5.3) ]. Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine. There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.

Use With Caution	Digoxin: Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are co-administered, inhibition of Pgp by clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range.
Oral Anticoagulants:

Use With Caution	Oral Anticoagulants: Spontaneous reports in the postmarketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously [see Warnings and Precautions (5.4) ].
Antiepileptics:

Use With Caution	Carbamazepine: Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered. Increased serum concentrations of carbamazepine were observed in clinical trials with clarithromycin. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with carbamazepine.
Antifungals:

Use With Caution	Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly (see also Itraconazole under “Drugs That Affect Clarithromycin” in the table below). Clarithromycin may increase the plasma concentrations of itraconazole. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions.

No Dose Adjustment	Fluconazole: [see Pharmacokinetics (12.3) ]
Anti-Gout Agents:

Contraindicated	Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. The dose of colchicine should be reduced when co-administered with clarithromycin in patients with normal renal and hepatic function [see Contraindications (4.4) and Warnings and Precautions (5.4) ].

Use With Caution
Antipsychotics:

Contraindicated	Pimozide: [see Contraindications (4.2) ]
Contraindicated
Quetiapine: Quetiapine is a substrate for CYP3A4, which is inhibited by clarithromycin. Co-administration with clarithromycin could result in increased quetiapine exposure and possible quetiapine related toxicities. There have been postmarketing reports of somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation during concomitant administration. Refer to quetiapine prescribing information for recommendations on dose reduction if co-administered with CYP3A4 inhibitors such as clarithromycin.
Antispasmodics:

Use With Caution	Tolterodine: The primary route of metabolism for tolterodine is via CYP2D6. However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when co-administered with clarithromycin.
Antivirals:

Use With Caution	Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3) ].

	Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction (see Saquinavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3) ].

Ritonavir, Etravirine: (see Ritonavir and Etravirine under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3) ].

Maraviroc: Clarithromycin may result in increases in maraviroc exposures by inhibition of CYP3A metabolism. See Selzentry^® prescribing information for dose recommendation when given with strong CYP3A inhibitors such as clarithromycin.

No Dose Adjustment	Boceprevir: Both clarithromycin and boceprevir are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when co-administered. No dose adjustments are necessary for patients with normal renal function (see Victrelis^® prescribing information).


Zidovudine: Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Administration of clarithromycin and zidovudine should be separated by at least two hours [see Pharmacokinetics (12.3) ].
Calcium Channel Blockers:

Use With Caution	Verapamil: Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil [see Warnings and Precautions (5.4) ].

	Amlodipine, Diltiazem: [see Warnings and Precautions (5.4) ]

Nifedipine: Nifedipine is a substrate for CYP3A. Clarithromycin and other macrolides are known to inhibit CYP3A. There is potential of CYP3A-mediated interaction between nifedipine and clarithromycin. Hypotension and peripheral edema were observed when clarithromycin was taken concomitantly with nifedipine [see Warnings and Precautions (5.4) ].
Ergot Alkaloids:

Contraindicated	Ergotamine, Dihydroergotamine: Postmarketing reports indicate that co-administration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4.6) ].
Gastroprokinetic Agents:

Contraindicated	Cisapride: [see Contraindications (4.2) ]
HMG-CoA Reductase Inhibitors:

Contraindicated	Lovastatin, Simvastatin, Atorvastatin, Pravastatin, Fluvastatin: [see Contraindications (4.5) and Warnings and Precautions (5.4) ]

Use With Caution

No Dose Adjustment
Hypoglycemic Agents:

Use With Caution	Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone: [see Warnings and Precautions (5.4) and Adverse Reactions (6.2) ]
Use With Caution
Insulin: [see Warnings and Precautions (5.4) and Adverse Reactions (6.2) ]
Immunosuppressants:

Use With Caution	Cyclosporine: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine.
Use With Caution
Tacrolimus: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with tacrolimus.
Phosphodiesterase Inhibitors:

Use With Caution	Sildenafil, Tadalafil, Vardenafil: Each of these phosphodiesterase inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant administration of clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil, or vardenafil will result in increased exposure of these phosphodiesterase inhibitors. Co-administration of these phosphodiesterase inhibitors with clarithromycin is not recommended. Increased systemic exposure of these drugs may occur with clarithromycin; reduction of dosage for phosphodiesterase inhibitors should be considered (see their respective prescribing information).
Proton Pump Inhibitors:

No Dose Adjustment	Omeprazole: The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when co-administered with clarithromycin as a result of increased omeprazole exposures [see Pharmacokinetics (12.3) ] (see also Omeprazole under “Drugs That Affect Clarithromycin” in the table below).
Xanthine Derivatives:

Use With Caution	Theophylline: Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations [see Pharmacokinetics (12.3) ]. Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range.
Triazolobenzodiazepines and Other Related Benzodiazepines:

Use With Caution	Midazolam: When oral midazolam is co-administered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated [see Warnings and Precautions (5.4) and Pharmacokinetics (12.3) ].
Use With Caution
Triazolam, Alprazolam: Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is co-administered with clarithromycin. There have been postmarketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested. In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines.

No Dose Adjustment	Temazepam, Nitrazepam, Lorazepam: For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.
Cytochrome P450 Inducers:

Use With Caution	Rifabutin: Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis (see Rifabutin under “Drugs That Affect Clarithromycin” in the table below).
Other Drugs Metabolized by CYP3A:

Use With Caution	There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort.
Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A:

Use With Caution	There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.

Drugs that Affect Clarithromycin
Drug(s) that Affect the Pharmacokinetics of Clarithromycin	Recommendation	Comments
Antifungals:

Use With Caution	Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions (see also Itraconazole under “Drugs That Are Affected By Clarithromycin” in the table above).
Antivirals:

Use With Caution	Atazanavir: When clarithromycin is co-administered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology (12.3) ]. Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.

	Ritonavir: Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with ritonavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium [see Pharmacokinetics (12.3) ]. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.

Saquinavir: When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (refer to ritonavir above) [see Pharmacokinetics (12.3) ].

Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.

No Dose Adjustment
Proton Pump Inhibitors:

Use With Caution	Omeprazole: Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole [see Pharmacokinetics (12.3) ].
Miscellaneous Cytochrome P450 Inducers:

Use With Caution	Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are Affected By Clarithromycin” in the table above).

Table name:

AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NCor25%increase^a	48%decrease
Carbamazepine(CBZ)	NC	40%decrease
CBZepoxide^b	NC	NE
Valproic acid	11%decrease	14%decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NCatTPM dosesupto400 mg/day	13%decrease

Table name:

Table 4. Mean (95% C.I.) maximal change in baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in healthy volunteers on daily alpha-blocker therapy
		Dosing of Vardenafil and Alpha-Blocker Separated by 6 Hours		Simultaneous dosing of Vardenafil and Alpha-Blocker
Alpha-Blocker		Vardenafil 10 mg Placebo-Subtracted	Vardenafil 20 mg Placebo-Subtracted	Vardenafil 10 mg Placebo-Subtracted	Vardenafil 20 mg Placebo-Subtracted
Terazosin 10 mg daily	Standing SBP	-7 (-10, -3)	-11 (-14, -7)	-23 (-31, 16) Due to the sample size, confidence intervals may not be an accurate measure for these data. These values represent the range for the difference.	-14 (-33, 11)
Terazosin 10 mg daily	Supine SBP	-5 (-8, -2)	-7 (-11, -4)	-7 (-25, 19)	-7 (-31, 22)
Tamsulosin 0.4 mg daily	Standing SBP	-4 (-8, -1)	-8 (-11, -4)	-8 (-14, -2)	-8 (-14, -1)
	Supine SBP	-4 (-8, 0)	-7 (-11, -3)	-5 (-9, -2)	-3 (-7, 0)

Table name:

Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion–the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine ( ≥ 1 µg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 µg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide(including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide(including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacological amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄, and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5’-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.

Table name:

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
* For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily*
Grapefruit juice	Avoid grapefruit juice

Table name: Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.

Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs that Interfere with Hemostasis
Clinical Impact:
Intervention:	Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention:	Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, or Beta-Blockers
Clinical Impact:
Intervention:
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention:	During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology (12.3)].
Intervention:	During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention:	The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.

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Calcium Channel Blockers	Antifungals	Antibiotics	Glucocorticoids	Other Drugs
diltiazem nicardipine verapamil	fluconazole itraconazole ketoconazole voriconazole	azithromycin clarithromycin erythromycin quinupristin/ dalfopristin	methylprednisolone	allopurinol amiodarone bromocriptine colchicine danazol imatinib metoclopramide nefazodone oral contraceptives

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Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3) , Table 5 for Magnitude of Interaction.
Drug Name	Effect on concentration of Nevirapine or Concomitant drug	Clinical Comment
Atazanavir/Ritonavir	↓ Atazanavir ↑ Nevirapine	Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure.
Clarithromycin	↓ Clarithromycin ↑ 14-OH clarithromycin	Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium- intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Efavirenz	↓ Efavirenz	There has been no determination of appropriate doses for the safe and effective use of this combination [see Warnings and Precautions (5.4) ].
Ethinyl estradiol and Norethindrone	↓ Ethinyl estradiol ↓ Norethindrone	Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended
Fluconazole	↑Nevirapine	Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine- associated adverse events.
Fosamprenavir	↓Amprenavir ↑Nevirapine	Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir	↓Amprenavir ↑Nevirapine	No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily.
Indinavir	↓ Indinavir	Appropriate doses for this combination are not established, but an increase in the dosage of indinavir may be required.
Ketoconazole	↓ Ketoconazole	Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Lopinavir/Ritonavir	↓Lopinavir	A dose increase of lopinavir/ritonavir tablets to 500/125 mg twice-daily is recommended when used in combination with nevirapine. A dose increase of lopinavir/ritonavir oral solution to 533/133 mg twice daily with food is recommended in combination with nevirapine. In children 6 months to 12 years of age receiving lopinavir/ritonavir solution, consideration should be given to increasing the dose of lopinavir/ritonavir to 13/3.25 mg/kg for those 7 to <15 kg; 11/2.75 mg/kg for those 15 to 45 kg; up to a maximum dose of 533/133 mg twice daily. Refer to the lopinavir/ritonavir package insert for complete pediatric dosing instructions when lopinavir/ritonavir tablets are used in combination with nevirapine.
Methadone	↓ Methadone	Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone- maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Nelfinavir	↓Nelfinavir M8 Metabolite ↓Nelfinavir C_min	The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established.
Rifabutin	↑Rifabutin	Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin	↓ Nevirapine	Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Saquinavir/Ritonavir	The interaction between Nevirapine and saquinavir/ritonavir has not been evaluated	The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
Potential Drug Interactions
Drug Class	Examples of Drugs
Antiarrhythmics	Amiodarone, disopyramide, lidocaine	Plasma concentrations may be decreased.
Anticonvulsants	Carbamazepine, clonazepam, ethosuximide	Plasma concentrations may be decreased.
Antifungals	Itraconazole	Plasma concentrations of some azole antifungals may be decreased. Nevirapine and itraconazole should not be administered concomitantly due to a potential decrease in itraconazole plasma concentrations.
Calcium channel blockers	Diltiazem, nifedipine, verapamil	Plasma concentrations may be decreased.
Cancer chemotherapy	Cyclophosphamide	Plasma concentrations may be decreased.
Ergot alkaloids	Ergotamine	Plasma concentrations may be decreased.
Immunosuppressants	Cyclosporin, tacrolimus, sirolimus	Plasma concentrations may be decreased.
Motility agents	Cisapride	Plasma concentrations may be decreased.
Opiate agonists	Fentanyl	Plasma concentrations may be decreased.
Antithrombotics	Warfarin	Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.

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Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs that Interfere with Hemostasis
Clinical Impact :	Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention :	Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact :	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention :	Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors , Angiotensin Receptor Blockers , or Beta - Blockers
Clinical Impact :	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention :	During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact :	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention :	During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Lithium
Clinical Impact :	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology (12.3)].
Intervention :	During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact :	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention :	During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact :	Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention :	During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact :	Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention :	The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact :	Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention :	During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.

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NA = Not available/reported
Digoxin concentrations increased greater than 50%
	Digoxin Serum Concentration Increase	Digoxin AUC Increase	Recommendations
Amiodarone	70%	NA	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
Captopril	58%	39%
Clarithromycin	NA	70%
Dronedarone	NA	150%
Gentamicin	129-212%	NA
Erythromycin	100%	NA
Itraconazole	80%	NA
Lapatinib	NA	180%
Nitrendipine	57%	15%
Propafenone	NA	60-270%
Quinidine	100%	NA
Ranolazine	50%	NA
Ritonavir	NA	86%
Telaprevir	50%	85%
Tetracycline	100%	NA
Verapamil	50-75%	NA
Digoxin concentrations increased less than 50%
Atorvastatin	22%	15%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
Carvedilol	16%	14%
Conivaptan	33%	43%
Diltiazem	20%	NA
Indomethacin	40%	NA
Nefazodone	27%	15%
Nifedipine	45%	NA
Propantheline	24%	24%
Quinine	NA	33%
Rabeprazole	29%	19%
Saquinavir	27%	49%
Spironolactone	25%	NA
Telmisartan	20-49%	NA
Ticagrelor	31%	28%
Tolvaptan	30%	20%
Trimethoprim	22-28%	NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate and sulfasalazine			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20-40% as necessary.

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Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of aripiprazole with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.8)].
Benzodiazepines(e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.8)].	Monitor sedation and blood pressure. Adjust dose accordingly.

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Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs that Interfere with Hemostasis
Clinical Impact :	Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention :	Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions ( 5 . 11)].
Aspirin
Clinical Impact :	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions ( 5 . 2)].
Intervention :	Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions ( 5 . 11)]. Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors , Angiotensin Receptor Blockers , or Beta - Blockers
Clinical Impact :	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention :	During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions ( 5 . 6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact :	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention :	During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions ( 5 . 6)].
Lithium
Clinical Impact :	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology ( 12 . 3)].
Intervention :	During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact :	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention :	During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact :	Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention :	During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact :	Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions ( 5 . 2)].
Intervention :	The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact :	Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention :	During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.

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Alcohol
Clinical Impact:	The concomitant use of alcohol with Oxymorphone Hydrochloride Tablets can result in an increase of oxymorphone plasma levels and potentially fatal overdose of oxymorphone.
Intervention:	Instruct patients not to consume alcoholic beverages or use prescription or non- prescription products containing alcohol while on Oxymorphone Hydrochloride Tablets therapy [see Clinical Pharmacology 12.3) ].
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines and other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [Warnings and Precautions (5.4)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Oxymorphone Hydrochloride Tablets if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)]. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Intervention:	The use of Oxymorphone Hydrochloride Tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of Oxymorphone Hydrochloride Tablets and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine,
Muscle Relaxants
Clinical Impact:	Oxymorphone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Oxymorphone Hydrochloride Tablets and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when Oxymorphone Hydrochloride Tablets are used concomitantly with anticholinergic drugs.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when Oxymorphone Hydrochloride Tablets are used concomitantly with anticholinergic drugs.
Cimetidine
Clinical Impact:	Cimetidine can potentiate opioid-induced respiratory depression.
Intervention:	Monitor patients for respiratory depression when Oxymorphone Hydrochloride Tablets and cimetidine are used concurrently.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when Oxymorphone Hydrochloride Tablets are used concomitantly with anticholinergic drugs.

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Not administered but an active metabolite of carbamazepine. *No significant effect.
Table 2 Steady-State Plasma Concentrations of Felbamate When Coadministered With Other AEDs
AED Coadministered	AED Concentration	Felbamate Concentration
Phenytoin	↑	↓
Valproate	↑	↔**
Carbamazepine (CBZ) *CBZ epoxide	↓ ↑	↓
Phenobarbital	↑	↓

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine, danazol	Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem	Do not exceed 40 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Figure 2: Effect of venlafaxine on the pharmacokinetics interacting drugs and their active metabolites.

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Table 6: Effects of Other Drugs/Substances on ASTAGRAF XL^a
^a ASTAGRAF XL dosage adjustment recommendation based on observed effect of coadministered drug on tacrolimus exposures [see Clinical Pharmacology (12.3)], literature reports of altered tacrolimus exposures, or the other drug’s known CYP3A inhibitor/inducer status ^b High dose or double strength grapefruit juice is a strong CYP3A inhibitor; low dose or single strength grapefruit juice is a moderate CYP3A inhibitor ^c Strong CYP3A inhibitor/inducer, based on reported effect on exposures to tacrolimus along with supporting in vitro CYP3A inhibitor/inducer data, or based on drug-drug interaction studies with midazolam (sensitive CYP3A probe substrate)
Drug/Substance Class or Name	Drug Interaction Effect	Recommendations
Grapefruit or grapefruit juice^b	May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.7, 5.10, 5.11)]	Avoid grapefruit or grapefruit juice
Alcohol	May increase the rate of tacrolimus release and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation ) [see Warnings and Precautions (5.7, 5.10, 5.11)]	Avoid alcoholic beverages
Strong CYP3A Inducers^c: Antimycobacterials (e.g., rifampin, rifabutin), anticonvulsants (e.g., phenytoin, carbamazepine and phenobarbital), St John’s Wort	May decrease tacrolimus whole blood trough concentrations and increase the risk of rejection [see Warnings and Precautions (5.10)]	Increase ASTAGRAF XL dose and monitor tacrolimus whole blood trough concentrations [see Dosage and Administration (2.3, 2.4) and Clinical Pharmacology (12.3)]
Strong CYP3A Inhibitors^c: Protease inhibitors (e.g, nelfinavir, telaprevir, boceprevir, ritonavir), azole antifungals (e.g., voriconazole, posaconazole, itraconazole, ketoconazole), antibiotics (e.g., clarithromycin, troleandomycin, chloramphenicol), nefazodone, schisandra sphenanthera extracts	May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.7, 5.10, 5.11)]	Reduce ASTAGRAF XL dose (for voriconazole and posaconazole, give one-third of the original dose) and adjust dose based on tacrolimus whole blood trough concentrations [see Dosage and Administration (2.3, 2.4) and Clinical Pharmacology (12.3)]
Mild or Moderate CYP3A Inhibitors: Clotrimazole, antibiotics (e.g., erythromycin, fluconazole), calcium channel blockers (e.g., verapamil, diltiazem, nifedipine, nicardipine), amiodarone, danazol, ethinyl estradiol, cimetidine, lansoprazole and omeprazole	May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.7, 5.10, 5.11)]	Monitor tacrolimus whole blood trough concentrations and reduce ASTAGRAF XL dose if needed [see Dosage and Administration (2.3, 2.4) and Clinical Pharmacology (12.3)]
Other drugs, such as: Magnesium and aluminum hydroxide antacids Metoclopramide	May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.7, 5.10, 5.11)]	Monitor tacrolimus whole blood trough concentrations and reduce ASTAGRAF XL dose if needed [see Dosage and Administration (2.3, 2.4) and Clinical Pharmacology (12.3)]
Mild or Moderate CYP3A Inducers Methylprednisolone, prednisone	May decrease tacrolimus concentrations	Monitor tacrolimus whole blood trough concentrations and adjust ASTAGRAF XL dose if needed [see Dosage and Administration (2.3, 2.4)]

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Concomitant Drug Name	Effect of Concomitant Drug on Carbamazepine	Clinical Recommendation
Aprepitant, cimetidine, ciprofloxacin, danazol, diltiazem, delavirdine, macrolides, erythromycin, troleandomycin, clarithromycin, fluoxetine, fluvoxamine, trazodone, olanzapine, loratadine, terfenadine, omeprazole, oxybutynin, dantrolene, isoniazid, niacinamide, nicotinamide, ibuprofen, propoxyphene, azoles (e.g., ketaconazole, itraconazole, fluconazole, voriconazole), acetazolamide, verapamil, ticlopidine, grapefruit juice, protease inhibitors	Increase in carbamazepine level (by CYP3A4 inhibition)	Closely monitor carbamazepine levels; dosage adjustment may be required
Cisplatin, doxorubicin HCl, felbamate, fosphenytoin, rifampin, phenobarbital, phenytoin, primidone, methsuximide, theophylline, aminophylline	Decrease in carbamazepine level (by CYP3A4 induction)
Loxapine, quetiapine and valproic acid	Decrease in carbamazepine level and increase in metabolite (carbamazepine-10,11-epoxide) levels (both by inhibition of human microsomal epoxide hydrolase)	Closely monitor carbamazepine levels; dosage adjustment may be required

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Table 2: Clinically Relevant Interactions Affecting Drugs Co-Administered with Rabeprazole Sodium Delayed-Release Tablets
Antiretrovirals
Clinical Impact:	The effect of PPI on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. • Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and nelfinavir) when used concomitantly with rabeprazole may reduce antiviral effect and promote the development of drug resistance. • Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with rabeprazole may increase toxicity. • There are other antiretroviral drugs which do not result in clinically relevant interactions with rabeprazole.
	Rilpivirine-containing products: Concomitant use with rabeprazole sodium delayed-release tablets are contraindicated [see CONTRAINDICATIONS (4)]. See prescribing information.
	Atazanavir: See prescribing information for atazanavir for dosing information.
Intervention:	Nelfinavir: Avoid concomitant use with rabeprazole sodium delayed-release tablets. See prescribing information for nelfinavir.
	Saquinavir: See the prescribing information for saquinavir and monitor for potential saquinavir toxicities.
	Other antiretrovirals: See prescribing information.
Warfarin
Clinical Impact:	Increased INR and prothrombin time in patients receiving PPIs, including rabeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death [see WARNINGS AND PRECAUTIONS (5.2)].
Intervention:	Monitor INR and prothrombin time. Dose adjustment of warfarin may be needed to maintain target INR range. See prescribing information for warfarin.
Methotrexate
Clinical Impact:	Concomitant use of rabeprazole with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of methotrexate with PPIs have been conducted [see WARNINGS AND PRECAUTIONS (5.9)].
Intervention:	A temporary withdrawal of rabeprazole sodium delayed-release tablets may be considered in some patients receiving high dose methotrexate administration.
Digoxin
Clinical Impact:	Potential for increased exposure of digoxin [see CLINICAL PHARMACOLOGY (12.3)].
Intervention:	Monitor digoxin concentrations. Dose adjustment of digoxin may be needed to maintain therapeutic drug concentrations. See prescribing information for digoxin.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole, itraconazole)
Clinical Impact:	Rabeprazole can reduce the absorption of drugs due to its effect on reducing intragastric acidity.
Intervention:	Mycophenolate mofetil (MMF): Co-administration of PPIs in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving PPIs and MMF. Use rabeprazole sodium delayed-release tablets with caution in transplant patients receiving MMF. See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:	Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:	See CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS in prescribing information for clarithromycin. See DRUG INTERACTIONS in prescribing information for amoxicillin.

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Table 6: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies [see Clinical Pharmacology (12.3) (Tables 12 and 13) for magnitude of interaction]
Concomitant Drug Class: Drug Name	Effect on Concentration	Clinical Comment
HIV Antiviral Agents: Reverse Transcriptase Inhibitors
Delavirdine	↑ nelfinavir (C_min) ↓ delavirdine	Concentrations of nelfinavir were increased while concentrations of delavirdine were decreased when the two agents were coadministered. Appropriate doses of the combination, with respect to safety and efficacy, have not been established.
Nevirapine	↓ nelfinavir (C_min)	Concentrations of nelfinavir were decreased when coadministered with nevirapine. An appropriate dose of nelfinavir with respect to safety and efficacy has not been established.
Didanosine	↔ nelfinavir	There was no change in nelfinavir concentration when coadministered with didanosine. However, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after VIRACEPT (given with food).
HIV Antiviral Agents: Protease Inhibitors
Indinavir	↑ nelfinavir ↑ indinavir	Concentrations of both indinavir and nelfinavir were increased when the two agents were coadministered. Appropriate doses for these combinations, with respect to safety and efficacy, have not been established.
Ritonavir	↑ nelfinavir ↔ ritonavir	Concentrations of nelfinavir were increased when coadministered with ritonavir. An appropriate dose of nelfinavir for this combination, with respect to safety and efficacy, has not been established.
Saquinavir	↑ nelfinavir ↑ saquinavir	Concentrations of both saquinavir and nelfinavir were increased when the two agents were coadministered. Appropriate doses for these combinations, with respect to safety and efficacy, have not been established.
ANTICOAGULANT
Warfarin	Warfarin	Coadministration of warfarin and VIRACEPT may affect concentrations of warfarin. It is recommended that the INR (international normalized ratio) be monitored carefully during treatment with VIRACEPT, especially when commencing therapy.
ANTICONVULSANTS
Carbamazepine Phenobarbital Phenytoin	↓ nelfinavir ↓ phenytoin	Concentrations of nelfinavir may be decreased. VIRACEPT may not be effective due to decreased nelfinavir plasma concentrations in patients taking these agents concomitantly. Phenytoin plasma/serum concentrations should be monitored; phenytoin dose may require adjustment to compensate for altered phenytoin concentration.
ANTIDEPRESSANT
Trazodone	↑ trazodone	Concomitant use of trazodone and VIRACEPT may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as VIRACEPT, the combination should be used with caution and a lower dose of trazodone should be considered.
ANTIGOUT
Colchicine	↑ colchicines	Patients with renal or hepatic impairment should not be given colchicine with VIRACEPT due to the risk of colchicine toxicity. Treatment of gout flares – co- administration of colchicine in patients on VIRACEPT: 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout-flares – coadministration of colchicine in patients on VIRACEPT: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF)– coadministration of colchicine in patients on VIRACEPT: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
ANTIMYCOBACTERIAL
Rifabutin	↑ rifabutin ↓ nelfinavir (750 mg TID) ↔ nelfinavir (1250 mg BID)	It is recommended that the dose of rifabutin be reduced to one-half the usual dose when administered with VIRACEPT; 1250 mg BID is the preferred dose of VIRACEPT when coadministered with rifabutin.
ENDOTHELIN RECEPTOR ANTAGONIST
Bosentan	↑ bosentan	Concentrations of bosentan may be increased when coadministered with VIRACEPT. Coadministration of bosentan in patients on VIRACEPT or coadministration of VIRACEPT in patients on bosentan: Start at or adjust bosentan to 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA REDUCTASE INHIBITORS
Atorvastatin Rosuvastatin	↑ atorvastatin ↑ rosuvastatin	Titrate atorvastatin dose carefully and use the lowest necessary dose; do not exceed atorvastatin 40 mg/day.
IMMUNOSUPPRESSANTS
Cyclosporine Tacrolimus Sirolimus	↑ immuno-suppressants ↑ nelfinavir	Concentrations of these immunosuppressants and nelfinavir may be increased by coadministration of these agents with nelfinavir.
INHALED BETA AGONIST
Salmeterol	↑ salmeterol	Concurrent administration of salmeterol with VIRACEPT is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
INHALED/NASAL STEROID
Fluticasone	↑ fluticasone	Concomitant use of fluticasone propionate and VIRACEPT may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use.
MACROLIDE ANTIBIOTIC
Azithromycin	↑ azithromycin	Dose adjustment of azithromycin is not recommended, but close monitoring for known side effects such as liver enzyme abnormalities and hearing impairment is warranted.
NARCOTIC ANALGESIC
Methadone	↓ methadone	Concentrations of methadone were decreased when coadministered with VIRACEPT. Dosage of methadone may need to be increased when coadministered with VIRACEPT.
HORMONAL CONTRACEPTIVES
Ethinyl estradiol Norethindrone	↓ ethinyl estradiol ↓ norethindrone	Concentrations of ethinyl estradiol and norethindrone were decreased when coadministered with VIRACEPT. Alternative or additional contraceptive measures should be used when oral contraceptives containing ethinyl estradiol or norethindrone and VIRACEPT are coadministered.
PDE5 INHIBITORS
Sildenafil Vardenafil Tadalafil	↑ PDE5 Inhibitors	Concomitant use of PDE5 inhibitors and VIRACEPT should be undertaken with caution. May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): • Use of sildenafil (REVATIO) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications (4)]. • The following dose adjustments are recommended for use of tadalafil (ADCIRCA™) with VIRACEPT: Coadministration of ADCIRCA in patients on VIRACEPT or coadministration of VIRACEPT in patients on ADCIRCA: Start at or adjust ADCIRCA to 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 24 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours, is recommended. Use with increased monitoring for adverse events.
PROTON PUMP INHIBITORS
Omeprazole	↓ nelfinavir	Omeprazole decreases the plasma concentrations of nelfinavir. Concomitant use of proton pump inhibitors and VIRACEPT may lead to a loss of virologic response and development of resistance.
ANTIPSYCHOTICS
Quetiapine	↑ quetiapine	Initiation of VIRACEPT in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine drug exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking VIRACEPT: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.

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Table 14: Clinically Important Drug Interactions: Effect of other Drugs on Guanfacine Extended-Release Tablets
Concomitant Drug Name or Drug Class	Clinical Rationale and Magnitude of Drug Interaction	Clinical Recommendation
Strong and moderate CYP3A4 inhibitors, e.g., ketoconazole, fluconazole	Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in an increase in exposure	Consider dose reduction [see Dosage and administration (2.7) ]
Strong and moderate CYP3A4 inducers, e.g., rifampin, efavirenz	Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in a 60% decrease in exposure	Consider dose increase[see Dosage and administration (2.7) ]

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Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.6).]
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported . Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [see Adverse Reactions (6.1).]
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution 2-fold increase in exposure	Monitor for sildenafil toxicity (see Pharmacokinetics -(12.3)-] .
Duloxetine	Avoid Use 5-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx ^® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2)].	Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

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Table 2: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 5 mg in BPH patients on stable alpha-blocker therapy (Study 1)
Alpha-Blocker		Simultaneous dosing of Vardenafil 5 mg and Alpha-Blocker, Placebo-Subtracted	Dosing of Vardenafil 5 mg and Alpha-Blocker Separated by 6 Hours, Placebo-Subtracted
Terazosin 5 or 10 mg daily	Standing SBP	-3 (-6.7, 0.1)	-4 (-7.4, -0.5)
Terazosin 5 or 10 mg daily	Supine SBP	-4 (-6.7, -0.5)	-4 (-7.1, -0.7)
Tamsulosin 0.4 mg daily	Standing SBP Supine SBP	-6 (-9.9, -2.1) -4 (-7.0, -0.8)	-4 (-8.3, -0.5) -5 (-7.9, -1.7)

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Table 7 Summary of AED Interactions with Oxcarbazepine
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400 to 2,000	900	nc¹nc denotes a mean change of less than 10%	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100 to 150	600 to 1,800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250 to 500	600 to 1,800 >1,200 to 2,400	nc ²Pediatrics up to 40% increase³Mean increase in adults at high oxcarbazepine doses[CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400 to 2,800	600 to 1,800	nc	18% decrease [CI: 13% decrease, 40% decrease]
Lamotrigine	200	1200	nc	nc

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Antiretrovirals
Clinical Impact:	The effect of PPI on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and nelfinavir) when used concomitantly with rabeprazole may reduce antiviral effect and promote the development of drug resistance. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with rabeprazole may increase toxicity. There are other antiretroviral drugs which do not result in clinically relevant interactions with rabeprazole.
Intervention:	Rilpivirine-containing products: Concomitant use with Rabeprazole Sodium Delayed-Release Tablets is contraindicated [see Contraindications (4)]. See prescribing information. Atazanavir: See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with Rabeprazole Sodium Delayed-Release Tablets. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir and monitor for potential saquinavir toxicities. Other antiretrovirals: See prescribing information.
Warfarin
Clinical Impact:	Increased INR and prothrombin time in patients receiving PPIs, including rabeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death [see Warnings and Precautions (5.2)].
Intervention:	Monitor INR and prothrombin time. Dose adjustment of warfarin may be needed to maintain target INR range. See prescribing information for warfarin.
Methotrexate
Clinical Impact:	Concomitant use of rabeprazole with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of methotrexate with PPIs have been conducted [see Warnings and Precautions (5.9)].
Intervention:	A temporary withdrawal of Rabeprazole Sodium Delayed-Release Tablets may be considered in some patients receiving high dose methotrexate administration.
Digoxin
Clinical Impact:	Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention:	Monitor digoxin concentrations. Dose adjustment of digoxin may be needed to maintain therapeutic drug concentrations. See prescribing information for digoxin.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole, itraconazole)
Clinical Impact:	Rabeprazole can reduce the absorption of drugs due to its effect on reducing intragastric acidity.
Intervention:	Mycophenolate mofetil (MMF): Co-administration of PPIs in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving PPIs and MMF. Use Rabeprazole Sodium Delayed-Release Tablets with caution in transplant patients receiving MMF. See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:	Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:	See Contraindications and Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.

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Interacting DrugInteracting Drug	InteractionInteraction
Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products ( 2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents	Carefully monitor blood glucose ( 5.12, 7.3)

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Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Amiodarone, verapamil, diltiazem	Do not exceed 10 mg simvastatin daily
Amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (> 1 quart daily)

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidibetic agents	Carefully monitor blood glucose (5.12, 7.3)

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Name of the Concomitant Drug	Change in the Concentration of Ganciclovir or Concomitant Drug	Clinical Comment
Zidovudine	↓ Ganciclovir ↑ Zidovudine	Zidovudine and valganciclovir tablets each have the potential to cause neutropenia and anemia
Probenicid	↑ Ganciclovir	Patients taking probenicid and valganciclovir tablets should be monitored for evidence of ganciclovir toxicity
Mycophenolate Mofetil (MMF)	↔ Ganciclovir (in patients with normal renal function) ↔ MMF (in patients with normal renal function)	Patients with renal impairment should be monitored carefully as levels of MMF metabolites and ganciclovir may increase
Didanosine	↓ Ganciclovir ↑ Didanosine	Patients should be closely monitored for didanosine toxicity

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Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 3: Summary of AED Interactions with Oxcarbazepine
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400-2000	900	ncnc denotes a mean change of less than 10%	40% decrease [CI:17% decrease, 57% decrease]
Phenobarbital	100-150	600-1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI:12% decrease, 51% decrease]
Phenytoin	250-500	600-1800 >1200-2400	nc ^, Pediatrics up to 40% increaseMean increase in adults at high Oxcarbazepine doses [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400-2800	600-1800	nc	18% decrease [CI:13% decrease, 40% decrease]

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Classes of Drugs
Adrenal Cortical Steroid Inhibitors Antacids Antianxiety Agents Antiarrhythmics† Antibiotics† Anticonvulsants† Antidepressants† Antihistamines Antineoplastics†	Antipsychotic Medications Antithyroid Drugs† Barbiturates Diuretics† Enteral Nutritional Supplements Fungal Medications, Systemic† Gastric Acidity and Peptic Ulcer Agents† Hypnotics†	Hypolipidemics† Bile Acid-Binding Resins† HMG-CoA Reductase Inhibitors† Immunosuppressives Oral Contraceptives, Estrogen Containing Selective Estrogen Receptor Modulators Steroids, Adrenocortical† Tuberculosis Agents† Vitamins†

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin	Monitor phenytoin level (7)
Methotrexate	Monitor for methotrexate toxicity (7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine (7)

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AED Co - administered	AED Concentration	Topiramate Concentration
Phenytoin	NCor25%increase ^a	48%decrease
Carbamazepine(CBZ)	NC	40%decrease
CBZepoxide ^b	NC	NE
Valproic acid	11%decrease	14%decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NCatTPM dosesupto400 mg/day	13%decrease

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AED Co - administered	AED Concentration	Topiramate Concentration
Phenytoin	NCor25%increase ^a	48%decrease
Carbamazepine(CBZ)	NC	40%decrease
CBZepoxide ^b	NC	NE
Valproic acid	11%decrease	14%decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NCatTPM dosesupto400 mg/day	13%decrease

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* The interaction between immediate-release nevirapine and the drug was evaluated in a clinical study. The results of drug interaction studies with immediate-release nevirapine are expected to also apply to nevirapine extended-release.
Drug Name	Effect on Concentration of Nevirapine or Concomitant Drug	Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir*	↓ Atazanavir ↑ Nevirapine	Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir*	↓ Amprenavir ↑ Nevirapine	Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir*	↓ Amprenavir ↑ Nevirapine	No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir*	↓ Indinavir	The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir*	↓ Lopinavir	Dosing in adult patients:A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients:Please refer to the Kaletra^® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir*	↓ Nelfinavir M8 Metabolite ↓ Nelfinavir C_min	The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/ritonavir	The interaction between nevirapine and saquinavir/ritonavir has not been evaluated	The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz*	↓ Efavirenz	The appropriate doses of these combinations with respect to safety and efficacy have not been established.
Delavirdine Etravirine Rilpivirine		Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.
Hepatitis C Antiviral Agents
Boceprevir	Plasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine.	Nevirapine and boceprevir should not be coadministered because decreases in boceprevir plasma concentrations may result in a reduction in efficacy.
Telaprevir	Plasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir.	Nevirapine and telaprevir should not be coadministered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in a reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events.
Other Agents
Analgesics: Methadone*	↓ Methadone	Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics: Amiodarone, disopyramide, lidocaine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Antibiotics: Clarithromycin*	↓ Clarithromycin ↑ 14-OH clarithromycin	Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Rifabutin*	↑ Rifabutin	Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin*	↓ Nevirapine	Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants: Carbamazepine, clonazepam, ethosuximide	Plasma concentrations of nevirapine and the anticonvulsant may be decreased.	Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals: Fluconazole*	↑ Nevirapine	Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Ketoconazole*	↓ Ketoconazole	Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Itraconazole	↓ Itraconazole	Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics: Warfarin	Plasma concentrations may be increased.	Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers: Diltiazem, nifedipine, verapamil	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Cancer chemotherapy: Cyclophosphamide	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Ergot alkaloids: Ergotamine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Motility agents: Cisapride	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Opiate agonists: Fentanyl	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Oral contraceptives: Ethinyl estradiol and Norethindrone*	↓ Ethinyl estradiol ↓ Norethindrone	Despite lower ethinyl estradiol and norethindrone exposures when coadministered with nevirapine, literature reports suggest that nevirapine has no effect on pregnancy rates among HIV-infected women on combined oral contraceptives. When coadministered with nevirapine extended-release tablets, no dose adjustment of ethinyl estradiol or norethindrone is needed when used in combination for contraception When oral contraceptives are used for hormonal regulation during nevirapine extended-release tablets therapy, the therapeutic effect of the hormonal therapy should be monitored.

Table 3: Clinically Relevant Interactions Affecting Drugs Co-Administered with Omeprazole and Interaction with Diagnostics
Antiretrovirals
Clinical Impact:	The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
Intervention:	Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications (4)]. Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:	Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention:	Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact:	Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].
Intervention:	A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact:	Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)]. There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention:	Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6)].
Citalopram
Clinical Impact:	Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention:	Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:	Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].
Intervention:	Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:	Potential for increased exposure of phenytoin.
Intervention:	Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:	Increased exposure of diazepam [see Clinical Pharmacology (12.3)].
Intervention:	Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:	Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention:	Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:	Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:	Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)]. See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:	Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:	See Contraindications, Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact:	Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention:	Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:	Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10), Clinical Pharmacology (12.2)].
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:	Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact:	There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:	An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:	There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:	Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.

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Figure 5: Mean Standing Systolic Blood Pressure Change from Baseline

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Table II. Clinically Significant Drug Interactions With Theophylline*
Drug	Type Of Interaction	Effect**
* Refer to PRECAUTIONS , Drug Interactions for further information regarding table. ** Average effect on steady-state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine	Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.
Alcohol	A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours.	30% increase
Allopurinol	Decreases theophylline clearance at allopurinol doses ≥600 mg/day.	25% increase
Aminoglutethimide	Increases theophylline clearance by induction of microsomal enzyme activity.	25% decrease
Carbamazepine	Similar to aminoglutethimide.	30% decrease
Cimetidine	Decreases theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase
Ciprofloxacin	Similar to cimetidine.	40% increase
Clarithromycin	Similar to erythromycin.	25% increase
Diazepam	Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.	Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram	Decreases theophylline clearance by inhibiting hydroxylation and demethylation.	50% increase
Enoxacin	Similar to cimetidine.	300% increase
Ephedrine	Synergistic CNS effects.	Increased frequency of nausea, nervousness, and insomnia.
Erythromycin	Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen	Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.	30% increase
Flurazepam	Similar to diazepam.	Similar to diazepam.
Fluvoxamine	Similar to cimetidine.	Similar to cimetidine.
Halothane	Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.	Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A	Decreases theophylline clearance.	100% increase
Isoproterenol (I.V.)	Increases theophylline clearance.	20% decrease
Ketamine	Pharmacologic	May lower theophylline seizure threshold.
Lithium	Theophylline increases renal lithium clearance.	Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam	Similar to diazepam.	Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.	20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine	Similar to disulfiram.	80% increase
Midazolam	Similar to diazepam.	Similar to diazepam.
Moricizine	Increases theophylline clearance.	25% decrease
Pancuronium	Theophylline may antagonize nondepolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.	Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline	Decreases theophylline clearance.	30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.	25% decrease after two weeks of concurrent Phenobarbital.
Phenytoin	Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.	Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone	Decreases theophylline clearance and pharmacologic interaction.	40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and pharmacologic interaction.	100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin	Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.	20 - 40% decrease
Sulfinpyrazone	Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.	20% decrease
Tacrine	Similar to cimetidine, also increases renal clearance of theophylline.	90% increase
Thiabendazole	Decreases theophylline clearance.	190% increase
Ticlopidine	Decreases theophylline clearance.	60% increase
Troleandomycin	Similar to erythromycin.	33 - 100% increase depending on troleandomycin dose.
Verapamil	Similar to disulfiram.	20% increase

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Table 25: Clinically Important Drug Interactions with Aripiprazole:
Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.8)].
Benzodiazepines (e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.8)].	Monitor sedation and blood pressure. Adjust dose accordingly.

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Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio Change relative to reference)		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	Cmax	Risperidone Dose Recommendation
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.10, 7.3)

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol,	famotidine	nizatidine
systemic and inhaled	felodipine	norfloxacin
amoxicillin	finasteride	ofloxacin
ampicillin,	hydrocortisone	omeprazole
with or without	isoflurane	prednisone, prednisolone
sulbactam	isoniazid	ranitidine
atenolol	isradipine	rifabutin
azithromycin	influenza vaccine	roxithromycin
caffeine,	ketoconazole	sorbitol
dietary ingestion	lomefloxacin	(purgative doses do not
cefaclor	mebendazole	inhibit theophylline
co-trimoxazole	medroxyprogesterone	absorption)
(trimethoprim and	methylprednisolone	sucralfate
sulfamethoxazole)	metronidazole	terbutaline, systemic
diltiazem	metoprolol	terfenadine
dirithromycin	nadolol	tetracycline
enflurane	nifedipine	tocainide

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products ( 2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents	Carefully monitor blood glucose ( 5.11, 7.3)

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Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine,danazol	Do not exceed 10 mg simvastatindaily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem	Do not exceed 40 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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DRUG	DESCRIPTION OF INTERACTION
Corticosteroids	Decreases plasma salicylate level; tapering doses of steroids may promote salicylism.
Acidifying Agents	Increases plasma salicylate level.
Alkanizing Agents	Decreased plasma salicylate levels.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3) , Table 5 for Magnitude of Interaction.
Drug Name	Effect on concentration of Nevirapine or Concomitant drug	Clinical Comment
Atazanavir/Ritonavir	↓ Atazanavir ↑ Nevirapine	Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure.
Clarithromycin	↓ Clarithromycin ↑ 14-OH clarithromycin	Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium- intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Efavirenz	↓ Efavirenz	There has been no determination of appropriate doses for the safe and effective use of this combination [see Warnings and Precautions (5.4) ].
Ethinyl estradiol and Norethindrone	↓ Ethinyl estradiol ↓ Norethindrone	Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended
Fluconazole	↑Nevirapine	Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine- associated adverse events.
Fosamprenavir	↓Amprenavir ↑Nevirapine	Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir	↓Amprenavir ↑Nevirapine	No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily.
Indinavir	↓ Indinavir	Appropriate doses for this combination are not established, but an increase in the dosage of indinavir may be required.
Ketoconazole	↓ Ketoconazole	Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Lopinavir/Ritonavir	↓Lopinavir	A dose increase of lopinavir/ritonavir tablets to 500/125 mg twice-daily is recommended when used in combination with nevirapine. A dose increase of lopinavir/ritonavir oral solution to 533/133 mg twice daily with food is recommended in combination with nevirapine. In children 6 months to 12 years of age receiving lopinavir/ritonavir solution, consideration should be given to increasing the dose of lopinavir/ritonavir to 13/3.25 mg/kg for those 7 to <15 kg; 11/2.75 mg/kg for those 15 to 45 kg; up to a maximum dose of 533/133 mg twice daily. Refer to the lopinavir/ritonavir package insert for complete pediatric dosing instructions when lopinavir/ritonavir tablets are used in combination with nevirapine.
Methadone	↓ Methadone	Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone- maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Nelfinavir	↓Nelfinavir M8 Metabolite ↓Nelfinavir C_min	The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established.
Rifabutin	↑Rifabutin	Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin	↓ Nevirapine	Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Saquinavir/Ritonavir	The interaction between Nevirapine and saquinavir/ritonavir has not been evaluated	The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
Potential Drug Interactions
Drug Class	Examples of Drugs
Antiarrhythmics	Amiodarone, disopyramide, lidocaine	Plasma concentrations may be decreased.
Anticonvulsants	Carbamazepine, clonazepam, ethosuximide	Plasma concentrations may be decreased.
Antifungals	Itraconazole	Plasma concentrations of some azole antifungals may be decreased. Nevirapine and itraconazole should not be administered concomitantly due to a potential decrease in itraconazole plasma concentrations.
Calcium channel blockers	Diltiazem, nifedipine, verapamil	Plasma concentrations may be decreased.
Cancer chemotherapy	Cyclophosphamide	Plasma concentrations may be decreased.
Ergot alkaloids	Ergotamine	Plasma concentrations may be decreased.
Immunosuppressants	Cyclosporin, tacrolimus, sirolimus	Plasma concentrations may be decreased.
Motility agents	Cisapride	Plasma concentrations may be decreased.
Opiate agonists	Fentanyl	Plasma concentrations may be decreased.
Antithrombotics	Warfarin	Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.

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Table 1: Drugs that may have their plasma concentrations increased by itraconazole
Drug Class	Contraindicated	Not Recommended	Use with Caution	Comments
	Under no circumstances is the drug to be coadministered with itraconazole, and up to two weeks after discontinuation of treatment with itraconazole.	It is recommended that the use of the drug be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If coadministration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of the interacting drug is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured. The label of the coadministered drug should be consulted for information on dose adjustment and adverse effects.	Careful monitoring is recommended when the drug is coadministered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of the interacting drug, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured. The label of the coadministered drug should be consulted for information on dose adjustment and adverse effects.
Alpha Blockers		tamsulosin
Analgesics	methadone		alfentanil, buprenorphine IV and sublingual, fentanyl, oxycodone, sufentanil	Methadone: The potential increase in plasma concentrations of methadone when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation and torsade de pointes. Fentanyl: The potential increase in plasma concentrations of fentanyl when coadministered with itraconazole may increase the risk of potentially fatal respiratory depression. Sufentanil: No human pharmacokinetic data of an interaction with itraconazole are available. In vitro data suggest that sufentanil is metabolized by CYP3A4 and so potentially increased sufentanil plasma concentrations would be expected when coadministered with itraconazole.
Antiarrhythmics	disopyramide, dofetilide, dronedarone, quinidine		digoxin	Disopyramide, dofetilide, dronedarone, quinidine: The potential increase in plasma concentrations of these drugs when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation.
Antibacterials	telithromycin, in subjects with severe renal impairment or severe hepatic impairment	rifabutin	telithromycin	Telithromycin: The potential increase in plasma concentrations of telithromycin in subjects with severe renal impairment or severe hepatic impairment, when coadministered with itraconazole may increase the risk of serious cardiovascular events including QT prolongation and torsade de pointes. Rifabutin: See also under ‘Drugs that may decrease itraconazole plasma concentrations’.
Anticoagulants and Antiplatelet Drugs	ticagrelor	apixaban, rivaroxaban	coumarins, cilostazol, dabigatran	Ticagrelor: The potential increase in plasma concentrations of ticagrelor may increase the risk of bleeding. Coumarins: Itraconazole may enhance the anticoagulant effect of coumarin-like drugs, such as warfarin.
Anticonvulsants		carbamazepine		Carbamazepine: In vivo studies have demonstrated an increase in plasma carbamazepine concentrations in subjects concomitantly receiving ketoconazole. Although there are no data regarding the effect of itraconazole on carbamazepine metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of itraconazole and carbamazepine may inhibit the metabolism of carbamazepine. See also under ‘Drugs that may decrease itraconazole plasma concentrations’.
Antidiabetics			repaglinide, saxagliptin
Antihelmintics and Antiprotozoals			praziquantel
Antimigraine Drugs	ergot alkaloids, such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine)		eletriptan	Ergot Alkaloids: The potential increase in plasma concentrations of ergot alkaloids when coadministered with itraconazole may increase the risk of ergotism, i.e., a risk for vasospasm potentially leading to cerebral ischemia and/or ischemia of the extremities.
Antineoplastics	irinotecan	axitinib, dabrafenib, dasatinib, ibrutinib, nilotinib, sunitinib trabectedin	bortezomib, busulphan, docetaxel, erlotinib, gefitinib, imatinib, ixabepilone, lapatinib, ponatinib, trimetrexate, vinca alkaloids	Irinotecan: The potential increase in plasma concentrations of irinotecan when coadministered with itraconazole may increase the risk of potentially fatal adverse events.
Antipsychotics, Anxiolytics and Hypnotics	lurasidone, oral midazolam, pimozide, triazolam		alprazolam, aripiprazole, buspirone, diazepam, haloperidol, midazolam IV, perospirone, quetiapine, ramelteon, risperidone	Midazolam, triazolam: Coadministration of itraconazole and oral midazolam, or triazolam may cause several-fold increases in plasma concentrations of these drugs. This may potentiate and prolong hypnotic and sedative effects, especially with repeated dosing or chronic administration of these agents. Pimozide: The potential increase in plasma concentrations of pimozide when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation and torsade de pointes.
Antivirals		simeprevir	maraviroc, indinavir, ritonavir, saquinavir	Indinavir, ritonavir: See also under ‘Drugs that may increase itraconazole plasma concentrations’.
Beta Blockers			nadolol
Calcium Channel Blockers	felodipine, nisoldipine		other dihydropyridines, verapamil	Calcium channel blockers canhave a negative inotropic effect which may be additive to those of itraconazole. The potential increase in plasma concentrations of calcium channel blockers when co-administered with itraconazole may increase the risk of congestive heart failure. Dihydropyridines: Concomitant administration of itraconazole may cause several-fold increases in plasma concentrations of dihydropyridines. Edema has been reported in patients concomitantly receiving itraconazole and dihydropyridine calcium channel blockers.
Cardiovascular Drugs, Miscellaneous	Ivabradine ranolazine	aliskiren, sildenafil, for the treatment of pulmonary hypertension	bosentan, riociguat	Ivabradine: The potential increase in plasma concentrations of ivabradine when administered with itraconazole may increase the risk of ivabradine-related adverse events, such as atrial fibrillation, bradycardia, sinus arrest and heart block. Ranolazine: The potential increase in plasma concentrations of ranolazine when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation.
Diuretics	eplerenone			Eplerenone: The potential increase in plasma concentrations of eplerenone when coadministered with itraconazole may increase the risk of hyperkalemia and hypotension.
Gastrointestinal Drugs	cisapride		aprepitant	Cisapride: The potential increase in plasma concentrations of cisapride when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation.
Immunosuppres sants		everolimus, temsirolimus	budesonide, ciclesonide, cyclosporine, dexamethasone, fluticasone, methylprednisolone, rapamycin (also known as sirolimus), tacrolimus
Lipid Regulating Drugs	lovastatin, simvastatin		atorvastatin	The potential increase in plasma concentrations of atorvastatin, lovastatin, and simvastatin when coadministered with itraconazole may increase the risk of skeletal muscle toxicity, including rhabdomyolysis.
Respiratory Drugs		salmeterol
Urological Drugs	fesoterodine, in subjects with moderate to severe renal impairment, or moderate to severe hepatic impairment, solifenacin, in subjects with severe renal impairment or moderate to severe hepatic impairment	darifenacin, vardenafil	fesoterodine. oxybutynin, sildenafil, for the treatment of erectile dysfunction, solifenacin, tadalafil, tolterodine	Fesoterodine: The potential increase in plasma concentrations of the fesoterodine active metabolite may be greater in subjects with moderate to severe renal impairment, or moderate to severe hepatic impairment, which may lead to an increased risk of adverse reactions. Solifenacin: The potential increase in plasma concentrations of solifenacin in subjects with severe renal impairment or moderate to severe hepatic impairment, when coadministered with itraconazole may increase the risk of serious cardiovascular events including QT prolongation.
Other	colchicine, in subjects with renal or hepatic impairment	colchicine, conivaptan, tolvaptan	cinacalcet	Colchicine: The potential increase in plasma concentrations of colchicine when coadministered with itraconazole may increase the risk of potentially fatal adverse events. Conivaptan and Tolvaptan: A safe and effective dose of either conivaptan or tolvaptan has not been established when coadministered with itraconazole.

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Bleeding times
Clinical Impact:	Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention:	This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact:	The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention:	Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact:	Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention:	This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.

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Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs that Interfere with Hemostasis
Clinical Impact :	Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention :	Monitor patients with concomitant use of Meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact :	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)].
Intervention :	Concomitant use of Meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors , Angiotensin Receptor Blockers , or Beta - Blockers
Clinical Impact :	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention :	During concomitant use of Meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of Meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact :	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention :	During concomitant use of Meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Lithium
Clinical Impact :	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [see Clinical Pharmacology (12.3)].
Intervention :	During concomitant use of Meloxicam and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact :	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention :	During concomitant use of Meloxicam and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact :	Concomitant use of Meloxicam and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention :	During concomitant use of Meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact :	Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention :	The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact :	Concomitant use of Meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention :	During concomitant use of Meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.

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Table 13. Established and Other Potentially Significant Drug Interactions
	Effect on
	Concentration of
	Lamotrigine or
Concomitant Drug	Concomitant Drug	Clinical Comment
Estrogen-containing oral	↓ lamotrigine	Decreased lamotrigine concentrations
contraceptive		approximately 50%.
preparations containing
30 mcg ethinylestradiol	↓ levonorgestrel	Decrease in levonorgestrel
and 150 mcg		component by 19%.
levonorgestrel
Carbamazepine	↓ lamotrigine	Addition of carbamazepine decreases
and carbamazepine epoxide		lamotrigine concentration
		approximately 40%.

	? carbamazepine epoxide	May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration
		approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC
		approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration
		approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration
		approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC
		approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations
		slightly more than 2-fold.
		There are conflicting study results
	? valproate	regarding effect of lamotrigine on
		valproate concentrations: 1) a mean 25%
		decrease in valproate concentrations in
		healthy volunteers, 2) no change in
		valproate concentrations in controlled
		clinical trials in patients with epilepsy.
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistatcontaining products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin dailyFor patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Inhibitors of CYP3A4 and CYP2D6
Clinical Impact:	The concomitant use of Oxycodone Hydrochloride Capsules and CYP3A4 inhibitors can increase the plasma concentration of oxycodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of Oxycodone Hydrochloride Capsules and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of Oxycodone Hydrochloride Capsules is achieved [see Warnings and Precautions ( 5.4 ) ]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the oxycodone plasma concentration will decrease [see Clinical Pharmacology ( 12.3 )], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to oxycodone.
Intervention:	If concomitant use is necessary, consider dosage reduction of Oxycodone Hydrochloride Capsules until stable drug effects are achieved.Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the Oxycodone Hydrochloride Capsules dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact:	The concomitant use of Oxycodone Hydrochloride Capsules and CYP3A4 inducers can decrease the plasma concentration of oxycodone [see Clinical Pharmacology ( 12.3 ) ], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to oxycodone [see Warnings and Precautions ( 5.4 ) ]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the oxycodone plasma concentration will increase [see Clinical Pharmacology ( 12.3 )], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention:	If concomitant use is necessary, consider increasing the Oxycodone Hydrochloride Capsule dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider Oxycodone Hydrochloride Capsule dosage reduction and monitor for signs of respiratory depression.
Examples	Rifampin, carbamazepine, phenytoin
Benzodiazepines and other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, increases the risk of respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions ( 5.5 )].
Examples	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin.
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Oxycodone Hydrochloride Capsules if serotonin syndrome is suspected.
Examples	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions ( 5.2 )].
Intervention:	The use of Oxycodone Capsules is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Examples	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of Oxycodone Hydrochloride Capsules and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples	butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Oxycodone may enhance the neuromuscular blocking action ofskeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Oxycodone Hydrochloride Capsules and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when Oxycodone Hydrochloride Capsules is used concomitantly with anticholinergic drugs.

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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	Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ Lamotrigine	Decreased Lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ Lamotrigine	Addition of carbamazepine decreases Lamotrigine concentration approximately 40%
	? carbamazepine epoxide	May increase CBZ epoxide levels.
Lopinavir/ritonavir	↓ Lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ Lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/Primidone	↓ Lamotrigine	Decreased Lamotrigine concentration approximately 40%
Phenytoin	↓ Lamotrigine	Decreased Lamotrigine concentration approximately 40%
Rifampin	↓ Lamotrigine	Decreased Lamotrigine AUC approximately 40%.
Valproate	↑ Lamotrigine	Increased Lamotrigine concentrations slightly more than 2-fold.
	? valproate	There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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^aDrugs That May Increase Tacrolimus Blood Concentrations
a) This table is not all inclusive.
b) In a study of 6 normal volunteers, a significant increase in tacrolimus oral bioavailability (14±5% vs. 30±8%) was observed with concomitant ketoconazole administration (200 mg). The apparent oral clearance of tacrolimus during ketoconazole administration was significantly decreased compared to tacrolimus alone (0.430±0.129 L/hr/kg vs. 0.148±0.043 L/hr/kg). Overall, IV clearance of tacrolimus was not significantly changed by ketoconazole coadministration, although it was highly variable between patients.
c) Lansoprazole (CYP2C19, CYP3A4 substrate) may potentially inhibit CYP3A4-mediated metabolism of tacrolimus and thereby substantially increase tacrolimus whole blood concentrations, especially in transplant patients who are intermediate or poor CYP2C19 metabolizers, as compared to those patients who are efficient CYP2C19 metabolizers.
Calcium	Antifungal	Macrolide
Channel Blockers	Agents	Antibiotics
diltiazem	clotrimazole	clarithromycin
nicardipine	fluconazole	erythromycin
nifedipine	itraconazole	troleandomycin
verapamil	ketoconazole^b voriconazole
Gastrointestinal	Other
Prokinetic Agents	Drugs
cisapride	bromocriptine
metoclopramide	chloramphenicol
	cimetidine
	cyclosporine
	danazol
	ethinyl estradiol
	methylprednisolone
	lansoprazole^c
	omeprazole
	protease inhibitors
	nefazodone
	magnesium-aluminum-hydroxide

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Table 25: Clinically Important Drug Interactions with Aripiprazole:
Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3) ].	With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION(2.7) ] .
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3) ] .	With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION(2.7) ] .
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.8) ] .
Benzodiazepines (e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepamalone [see WARNINGS AND PRECAUTIONS (5.8 )]	Monitor sedation and blood pressure. Adjust dose accordingly.

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Digoxin concentrations increased greater than 50%
	Digoxin Serum Concentration Increase	Digoxin AUC Increase	Recommendations
Amiodarone	70%	NA	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30% to 50% or by modifying the dosing frequency and continue monitoring.
Captopril	58%	39%
Clarithromycin	NA	70%
Dronedarone	NA	150%
Gentamicin	129 to 212%	NA
Erthromycin	100%	NA
Itraconazole	60%	NA
Lapatinib	NA	180%
Propafenone	NA	60 to 270 %
Quinidine	100%	NA
Ranolazine	50%	NA
Ritonavir	NA	86%
Telaprevir	50%	85%
Tetracycline	100%	NA
Verapamil	50 to 75%	NA
Digoxin concentrations increased less than 50%
Atorvastatin	22%	15%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15% to 30% or by modifying the dosing frequency and continue monitoring.
Carvedilol	16%	14%
Conivaptan	33%	43%
Diltiazem	20%	NA
Indomethacin	40%	NA
Nefazodone	27%	15%
Nifedipine	45%	NA
Propantheline	24%	24%
Quinine	NA	33%
Rabeprazole	29%	19%
Saquinavir	27%	49%
Spironolactone	25%	NA
Telmisartan	20 to 49%	NA
Ticagrelor	31%	28%
Tolvaptan	30%	20%
Trimethoprim	22 to28%	NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate, and sulfasalazine			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20 % to 40 % as necessary.

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)	Do not exceed 40 mg atorvastatin daily

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Table II. Clinically significant drug interactions with theophylline*.
Drug		Type of Interaction	Effect**
*Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
**Average effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine		Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.
Alcohol		A single large dose of alcohol (3 ml/kg of whiskey) decreases theophylline clearance for up to 24 hours.	30% increase
Allopurinol		Decreases theophylline clearance at allopurinol doses >600 mg/day.	25% increase
Amino glutethimide		Increases theophylline clearance by induction of microsomal enzyme activity.	25% decrease
Carbamazepine		Similar to aminoglutethimide.	30% decrease
Cimetidine		Decreases theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase
Ciprofloxacin		Similar to cimetidine.	40% increase
Clarithromycin		Similar to erythromycin.	25% increase
Diazepam		Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.	Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram		Decreases theophylline clearance by inhibiting hydroxylation and demethylation.	50% increase
Enoxacin		Similar to cimetidine.	300% increase
Ephedrine		Synergistic CNS effects	Increased frequency of nausea, nervousness, and insomnia.
Erythromycin		Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen		Estrogen containing oral contraceptives decrease theophylline clearance in a dose- dependent fashion. The effect of progesterone on theophylline clearance is unknown.	30% increase
Flurazepam		Similar to diazepam.	Similar to diazepam.
Fluvoxamine		Similar to cimetidine	Similar to cimetidine
Halothane		Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.	Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A		Decreases theophylline clearance.	100% increase
Isoproterenol (IV)	Increases theophylline clearance.		20% decrease
Ketamine	Pharmacologic		May lower theophylline seizure threshold.
Lithium	Theophylline increases renal lithium clearance.		Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam	Similar to diazepam.		Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.		20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine	Similar to disulfiram.		80% increase
Midazolam	Similar to diazepam.		Similar to diazepam.
Moricizine	Increases theophylline clearance.		25% decrease
Pancuronium	Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.		Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline	Decreases theophylline clearance.		30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.		25% decrease after two weeks of concurrent PB.
Phenytoin	Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.		Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone	Decreases theophylline clearance and pharmacologic interaction.		40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and pharmacologic interaction.		100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin	Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.		20-40% decrease
Sulfinpyrazone	Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.		20% decrease
Tacrine	Similar to cimetidine, also increases renal clearance of theophylline.		90% increase
Thiabendazole	Decreases theophylline clearance.		190% increase
Ticlopidine	Decreases theophylline clearance.		60% increase
Troleandomycin	Similar to erythromycin.		33-100% increase depending on troleandomycin dose.
Verapamil	Similar to disulfiram.		20% increase

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Figure 7: Mean Standing Systolic Blood Pressure Change from Baseline

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Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
* Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing.
	20 mg/day	4 mg/day	1.6	-	Do not exceed 8 mg/day
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed

Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Table 4. Mean (95% C.I.) maximal change in baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in healthy volunteers on daily alpha-blocker therapy
		Dosing of Vardenafil and Alpha-Blocker Separated by 6 Hours		Simultaneous dosing of Vardenafil and Alpha-Blocker
Alpha-Blocker		Vardenafil 10 mg Placebo-Subtracted	Vardenafil 20 mg Placebo-Subtracted	Vardenafil 10 mg Placebo-Subtracted	Vardenafil 20 mg Placebo-Subtracted
Terazosin 10 mg daily	Standing SBP	-7 (-10, -3)	-11 (-14, -7)	-23 (-31, 16) Due to the sample size, confidence intervals may not be an accurate measure for these data. These values represent the range for the difference.	-14 (-33, 11)
Terazosin 10 mg daily	Supine SBP	-5 (-8, -2)	-7 (-11, -4)	-7 (-25, 19)	-7 (-31, 22)
Tamsulosin 0.4 mg daily	Standing SBP	-4 (-8, -1)	-8 (-11, -4)	-8 (-14, -2)	-8 (-14, -1)
	Supine SBP	-4 (-8, 0)	-7 (-11, -3)	-5 (-9, -2)	-3 (-7, 0)

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Table 13 Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine concentrations approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine and epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
	? Carbamazepine epoxide	May increase Carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
	? valproate	There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Table 3: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [See Clinical Pharmacology (12.3)]
Concomitant Drug Class: Drug Name	Effect on Concentration of Etravirine or Concomitant Drug	Clinical Comment
↑ = increase, ↓ = decrease, ↔ = no change
HIV-Antiviral Agents: Integrase Strand Inhibitors
dolutegravirThe interaction between INTELENCE^® and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.	↓ dolutegravir ↔ etravirine	Etravirine significantly reduced plasma concentrations of dolutegravir. Using cross-study comparisons to historical pharmacokinetic data for etravirine, dolutegravir did not appear to affect the pharmacokinetics of etravirine.
dolutegravir/darunavir/ritonavir	↓ dolutegravir ↔ etravirine	The effect of etravirine on dolutegravir plasma concentrations was mitigated by co-administration of darunavir/ritonavir or lopinavir/ritonavir, and is expected to be mitigated by atazanavir/ritonavir. Dolutegravir should only be used with INTELENCE^® when co-administered with atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir.
dolutegravir/lopinavir/ritonavir	↔ dolutegravir ↔ etravirine
HIV-Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
efavirenz nevirapine	↓ etravirine	Combining two NNRTIs has not been shown to be beneficial. Concomitant use of INTELENCE^® with efavirenz or nevirapine may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE^®. INTELENCE^® and other NNRTIs should not be co-administered.
delavirdine	↑ etravirine	Combining two NNRTIs has not been shown to be beneficial. INTELENCE^® and delavirdine should not be co-administered.
rilpivirine	↓ rilpivirine ↔ etravirine	Combining two NNRTIs has not been shown to be beneficial. INTELENCE^® and rilpivirine should not be coadministered.
HIV-Antiviral Agents: Protease Inhibitors (PIs)
atazanavir (without ritonavir)	↓ atazanavir	INTELENCE^® should not be co-administered with atazanavir without low-dose ritonavir.
atazanavir/ritonavir	↓ atazanavir ↔ etravirine	Concomitant use of INTELENCE^® with atazanavir/ritonavir decreased atazanavir C_min but it is not considered clinically relevant.. The mean systemic exposure (AUC) of etravirine after co-administration of INTELENCE^® with atazanavir/ritonavir in HIV-infected patients was similar to the mean systemic exposure of etravirine observed in the Phase 3 trials after co-administration of INTELENCE^® and darunavir/ritonavir (as part of the background regimen). INTELENCE^® and atazanavir/ritonavir can be co-administered without dose adjustments.
darunavir/ritonavir	↓ etravirine	The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE^® was co-administered with darunavir/ritonavir. Because all subjects in the Phase 3 trials received darunavir/ritonavir as part of the background regimen and etravirine exposures from these trials were determined to be safe and effective, INTELENCE^® and darunavir/ritonavir can be co-administered without dose adjustments.
fosamprenavir (without ritonavir)	↑ amprenavir	Concomitant use of INTELENCE^® with fosamprenavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of amprenavir. INTELENCE^® should not be co-administered with fosamprenavir without low-dose ritonavir.
fosamprenavir/ritonavir	↑ amprenavir	Due to a significant increase in the systemic exposure of amprenavir, the appropriate doses of the combination of INTELENCE^® and fosamprenavir/ritonavir have not been established. INTELENCE^® and fosamprenavir/ritonavir should not be co-administered.
indinavir (without ritonavir)	↓ indinavir	Concomitant use of INTELENCE^® with indinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of indinavir. INTELENCE^® should not be co-administered with indinavir without low-dose ritonavir.
lopinavir/ritonavir	↓ etravirine	The mean systemic exposure (AUC) of etravirine was reduced after co-administration of INTELENCE^® with lopinavir/ritonavir (tablet). Because the reduction in the mean systemic exposures of etravirine in the presence of lopinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE^® and lopinavir/ritonavir can be co-administered without dose adjustments.
nelfinavir (without ritonavir)	↑ nelfinavir	Concomitant use of INTELENCE^® with nelfinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of nelfinavir. INTELENCE^® should not be co-administered with nelfinavir without low-dose ritonavir.
ritonavir	↓ etravirine	Concomitant use of INTELENCE^® with ritonavir 600 mg twice daily may cause a significant decrease in the plasma concentration of etravirine and loss of therapeutic effect of INTELENCE^®. INTELENCE^® and ritonavir 600 mg twice daily should not be co-administered.
saquinavir/ritonavir	↓ etravirine	The mean systemic exposure (AUC) of etravirine was reduced when INTELENCE^® was co-administered with saquinavir/ritonavir. Because the reduction in the mean systemic exposures of etravirine in the presence of saquinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, INTELENCE^® and saquinavir/ritonavir can be co-administered without dose adjustments.
tipranavir/ritonavir	↓ etravirine	Concomitant use of INTELENCE^® with tipranavir/ritonavir may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of INTELENCE^®. INTELENCE^® and tipranavir/ritonavir should not be co-administered.
CCR5 Antagonists
maraviroc	↔ etravirine ↓ maraviroc	When INTELENCE^® is co-administered with maraviroc in the absence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 600 mg twice daily. No dose adjustment of INTELENCE^® is needed.
maraviroc/darunavir/ritonavir The reference for etravirine exposure is the pharmacokinetic parameters of etravirine in the presence of darunavir/ritonavir	↔ etravirine ↑ maraviroc	When INTELENCE^® is co-administered with maraviroc in the presence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 150 mg twice daily. No dose adjustment of INTELENCE^® is needed.
Other Agents
Antiarrhythmics: digoxin	↔ etravirine ↑ digoxin	For patients who are initiating a combination of INTELENCE^® and digoxin, the lowest dose of digoxin should initially be prescribed. For patients on a stable digoxin regimen and initiating INTELENCE^®, no dose adjustment of either INTELENCE^® or digoxin is needed. The serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.
amiodarone, bepridil, disopyramide, flecainide, lidocaine (systemic), mexiletine, propafenone, quinidine	↓ antiarrhythmics	Concentrations of these antiarrhythmics may be decreased when co-administered with INTELENCE^®. INTELENCE^® and antiarrhythmics should be co-administered with caution. Drug concentration monitoring is recommended, if available.
Anticoagulants: warfarin	↑ anticoagulants	Warfarin concentrations may be increased when co-administered with INTELENCE^®. The international normalized ratio (INR) should be monitored when warfarin is combined with INTELENCE^®.
Anticonvulsants: carbamazepine, phenobarbital, phenytoin	↓ etravirine	Carbamazepine, phenobarbital and phenytoin are inducers of CYP450 enzymes. INTELENCE^® should not be used in combination with carbamazepine, phenobarbital, or phenytoin as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE^®.
Antifungals: fluconazole, voriconazole	↑ etravirine ↔ fluconazole ↑ voriconazole	Co-administration of etravirine and fluconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and fluconazole should be co-administered with caution. No dose adjustment of INTELENCE^® or fluconazole is needed.
		Co-administration of etravirine and voriconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and voriconazole should be co-administered with caution. No dose adjustment of INTELENCE^® or voriconazole is needed.
Antifungals: itraconazole, ketoconazole, posaconazole	↑ etravirine ↓ itraconazole ↓ ketoconazole ↔ posaconazole	Posaconazole, a potent inhibitor of CYP3A4, may increase plasma concentrations of etravirine. Itraconazole and ketoconazole are potent inhibitors as well as substrates of CYP3A4. Concomitant systemic use of itraconazole or ketoconazole and INTELENCE^® may increase plasma concentrations of etravirine. Simultaneously, plasma concentrations of itraconazole or ketoconazole may be decreased by INTELENCE^®. Dose adjustments for itraconazole, ketoconazole or posaconazole may be necessary depending on the other co-administered drugs.
Antiinfectives: clarithromycin	↑ etravirine ↓ clarithromycin ↑ 14-OH-clarithromycin	Clarithromycin exposure was decreased by INTELENCE^®; however, concentrations of the active metabolite, 14-hydroxy-clarithromycin, were increased. Because 14-hydroxy-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered for the treatment of MAC.
Antimalarials: artemether/lumefantrine	↔ etravirine ↓ artemether ↓ dihydroartemisinin ↓ lumefantrine	Caution is warranted when co-administering INTELENCE® and artemether/lumefantrine as it is unknown whether the decrease in exposure of artemether or its active metabolite, dihydroartemisinin, could result in decreased antimalarial efficacy. No dose adjustment is needed for INTELENCE^®.
Antimycobacterials: rifampin, rifapentine	↓ etravirine	Rifampin and rifapentine are potent inducers of CYP450 enzymes. INTELENCE^® should not be used with rifampin or rifapentine as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE^®.
Antimycobacterials: rifabutin	↓ etravirine ↓ rifabutin ↓ 25-O-desacetylrifabutin	If INTELENCE^® is NOT co-administered with a protease inhibitor/ritonavir, then rifabutin at a dose of 300 mg once daily is recommended. If INTELENCE^® is co-administered with darunavir/ritonavir, lopinavir/ritonavir or saquinavir/ritonavir, then rifabutin should not be co-administered due to the potential for significant reductions in etravirine exposure.
Benzodiazepines: diazepam	↑ diazepam	Concomitant use of INTELENCE^® with diazepam may increase plasma concentrations of diazepam. A decrease in diazepam dose may be needed.
Corticosteroids: dexamethasone (systemic)	↓ etravirine	Systemic dexamethasone induces CYP3A and can decrease etravirine plasma concentrations. This may result in loss of therapeutic effect of INTELENCE^®. Systemic dexamethasone should be used with caution or alternatives should be considered, particularly for long-term use.
Herbal Products: St. John's wort (Hypericum perforatum)	↓ etravirine	Concomitant use of INTELENCE^® with products containing St. John's wort may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of INTELENCE^®. INTELENCE^® and products containing St. John's wort should not be co-administered.
Hepatitis C Virus (HCV) Direct-Acting Antivirals: boceprevir	↓etravirine ↑ boceprevir	The combination of INTELENCE^® and boceprevir can be used without dose adjustments. However, co-administration of INTELENCE® and boceprevir is not recommended in the presence of other drugs which may further decrease etravirine exposure. This includes, but is not limited to, darunavir/ritonavir, lopinavir/ritonavir, saquinavir/ritonavir, tenofovir disoproxil fumarate, or rifabutin.
telaprevir	↔ etravirine ↓ telaprevir	There are insufficient data to make a dosing recommendation for telaprevir when used with INTELENCE^®.
HMG-CoA Reductase Inhibitors: atorvastatin fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin	↔ etravirine ↓ atorvastatin ↑ 2-OH-atorvastatin ↔ etravirine ↑ fluvastatin, ↓ lovastatin, ↑ pitavastatin, ↔ pravastatin, ↔ rosuvastatin, ↓ simvastatin	The combination of INTELENCE^® and atorvastatin can be given without dose adjustments, however, the dose of atorvastatin may need to be altered based on clinical response. No interaction between pravastatin, rosuvastatin and INTELENCE^® is expected. Lovastatin and simvastatin are CYP3A substrates and co-administration with INTELENCE^® may result in lower plasma concentrations of the HMG-CoA reductase inhibitor. Fluvastatin and pitavastatin are metabolized by CYP2C9 and co-administration with INTELENCE^® may result in higher plasma concentrations of the HMG-CoA reductase inhibitor. Dose adjustments for these HMG-CoA reductase inhibitors may be necessary.
Immunosuppressants: cyclosporine, sirolimus, tacrolimus	↓ immunosuppressant	INTELENCE^® and systemic immunosuppressants should be co-administered with caution because plasma concentrations of cyclosporine, sirolimus, or tacrolimus may be affected.
Narcotic Analgesics/Treatment of Opioid Dependence: buprenorphine, buprenorphine/naloxone, methadone	↔ etravirine ↓ buprenorphine ↔ norbuprenorphine ↔ methadone	INTELENCE^® and buprenorphine (or buprenorphine/naloxone) can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as buprenorphine (or buprenorphine/naloxone) maintenance therapy may need to be adjusted in some patients. INTELENCE^® and methadone can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as methadone maintenance therapy may need to be adjusted in some patients.
Phosphodiesterase Type 5 (PDE-5) Inhibitors: sildenafil, tadalafil, vardenafil	↓ sildenafil ↓ N-desmethyl-sildenafil	INTELENCE^® and sildenafil can be co-administered without dose adjustments, however, the dose of sildenafil may need to be altered based on clinical effect.
Platelet Aggregation Inhibitors: clopidogrel	↓ clopidogrel (active) metabolite	Activation of clopidogrel to its active metabolite may be decreased when clopidogrel is co-administered with INTELENCE^®. Alternatives to clopidogrel should be considered.

Table name:

Table II. Clinically significant drug interactions with theophylline.*
Drug	Type of Interaction	Effect†
Adenosine	Theophylline blocks adenosine receptors.	Higher doses of adenosine may berequired to achieve desired effect.
Alcohol	A single large dose of alcohol (3 mL/kg ofwhiskey) decreases theophylline clearance for up to24 hours	30% increase
Allopurinol	Decreases theophylline clearance at allopurinoldoses 600 mg/day	25% increase
Aminoglutethimide	Increases theophylline clearance by induction ofmicrosomal enzyme activity.	25% decrease
Carbamazepine	Similar to aminoglutethimide.	30% decrease
Cimetidine	Decreases theophylline clearance by inhibitingcytochrome P450 1A2	70% increase
Ciprofloxacin	Similar to cimetidine.	40% increase
Clarithromycin	Similar to erythromycin.	25% increase
Diazepam	Benzodiazepines increase CNS concentratrionsof adenosine, a potent CNS depressant, whiletheophylline blocks adenosine receptors.	Larger diazepam doses may be requiredto produce desired level of sedation.Discontinuation of theophylline withoutreduction of diazepam dose may resultin respiratory depression.
Disulfiram	Decreases theophylline clearance by inhibitinghydroxylation and demethylation.	50% increase
Enoxacin	Similar to cimetidine.	300% increase
Ephedrine	Synergistic CNS effects	Increased frequency of nausea,nervousness, and insomnia.
Erythromycin	Erythromycin metabolite decreases theophyllineclearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-state serum concentrations decrease by asimilar amount.
Estrogen	Estrogen containing oral contraceptives decreasetheophylline clearance in a dose-dependentfashion. The effect of progesterone on theophyllineclearance in unknown.	30% increase
Flurazepam	Similar to diazepam.	Similar to diazepam.
Fluvoxamine	Similar to cimetidine.	Similar to cimetidine.
Halothane	Halothane sensitizes the myocardium tocatecholamines, theophylline increases release ofendogenous catecholamines.	Increased risk of ventriculararrhythmias.
Interferon, human recombinant alpha-A	Decreases theophylline clearance.	100% increase
Isoproterenol (IV)	Increase theophylline clearance.	20% increase
Ketamine	Pharmacologic	May lower theophylline seizurethreshold.
Lithium	Theophylline increases renal lithium clearance.	Lithium dose required to achievea therapeutic serum concentrationincreased an average of 60%.
Lorazepam	Similar to diazepam.	Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.	20% increase after low dose MTX,higher dose MTX may have a greatereffect.
Mexiletine	Similar to disulfiram.	80% increase
Midazolam	Similar to diazepam.	Similar to diazepam.
Moricizine	Increases theophylline clearance.	25% increase
Pancuronium	Theophylline may antagonize non-depolarizingneuromuscular blocking effects;possibly due tophosphodiesterase inhibition.	Larger dose of pancuronium may berequired to achieve neuromuscularblockade.
Pentoxifylline	Decreases theophylline clearance.	30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.	25% decrease after two weeks ofconcurrent PB.
Phenytoin	Phenytoin increases theophylline clearance byincreasing microsomal enzyme activity.	Serum theophylline and phenytoinconcentrations decrease about 40%.
Propafenone	Decreases theophylline clearance andpharmacologic interaction.	40% increase. Beta-2 blocking effectmay decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and pharmacologicinteraction.	100% increase Beta-2 blocking effectmay decrease efficacy of theophylline
Rifampin	Increases theophylline clearance by increasingcytochrome P450 1A2 and 3A3 activity.	20-40% decrease
Sulfinpyrazone	Increase theophylline clearance by increasingdemethylation and hydroxylation. Decreases renalclearance of theophylline.	20% increase
Tacrine	Similar to cimetidine, also increases renalclearance of theophylline.	90% increase
Thiabendazole	Decreases theophylline clearance.	190% increase
Ticlopidine	Decreases theophylline clearance.	60% increase
Troleandomycin	Similar to erythromycin.	33-100% increase depending ontroleandomycin dose.
Verapamil	Similar to disulfiram.	20% increase

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Drugs That Interfere with Hemostasis
Clinical Impact:	Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of indomethacin extended-release capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11) ].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2) ].
Intervention:	Concomitant use of indomethacin extended-release capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11) ]. Indomethacin extended-release capsules are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of indomethacin extended-release capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of indomethacin extended-release capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6) ]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. It has been reported that the addition of triamterene to a maintenance schedule of indomethacin extended-release capsules resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin extended-release capsules and triamterene should not be administered together. Both indomethacin extended-release capsules and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin extended-release capsules and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently.
Intervention:	Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin extended-release capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels [see Warnings and Precautions (5.6) ].
Digoxin
Clinical Impact:	The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of indomethacin extended-release capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of indomethacin extended-release capsules and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of indomethacin extended-release capsules and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of indomethacin extended-release capsules and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of indomethacin extended-release capsules and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin. [see Clinical Pharmacology (12.3) ]. In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage.
Intervention:	The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of indomethacin extended-release capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of indomethacin extended-release capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Probenecid
Clinical Impact:	When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased.
Intervention:	During the concomitant use of indomethacin extended-release capsules and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Table 6: Predicted Drug Interactions with VIDEX EC
Drug or Drug Class	Effect	Clinical Comment
↑ Indicates increase. ^a Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of VIDEX EC is recommended [see Warnings and Precautions (5.1) ]. ^b [See Warnings and Precautions (5.6) .]
Drugs that may cause pancreatic toxicity	↑ risk of pancreatitis	Use only with extreme caution.^a
Neurotoxic drugs	↑ risk of neuropathy	Use with caution.^b

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Calcium Channel Blockers	Antifungals	Antibiotics	Glucocorticoids	Other Drugs
diltiazem	fluconazole	azithromycin	methylprednisolone	allopurinol
nicardipine	itraconazole	clarithromycin		amiodarone
verapamil	ketoconazole	erythromycin		bromocriptine
	voriconazole	quinupristin/		colchicine
		dalfopristin		danazol
				imatinib
				metoclopramide
				nefazodone
				oral contraceptives

Table name:

AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide Is not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

Table name:

Table II. Clinically significant drug interactions with theophylline.Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
Drug	Type of Interaction	EffectAverage effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine	Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.
Alcohol	A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours.	30% increase
Allopurinol	Decreases theophylline clearance at allopurinol doses greater than or equal to 600 mg/day.	25% increase
Aminoglutethimide	Increases theophylline clearance by induction of microsomal enzyme activity.	25% decrease
Carbamazepine	Similar to aminoglutethimide.	30% decrease
Cimetidine	Decreases theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase
Ciprofloxacin	Similar to cimetidine.	40% increase
Clarithromycin	Similar to erythromycin.	25% increase
Diazepam	Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.	Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram	Decreases theophylline clearance by inhibiting hydroxylation and demethylation.	50% increase
Enoxacin	Similar to cimetidine.	300% increase
Ephedrine	Synergistic CNS effects.	Increased frequency of nausea, nervousness, and insomnia.
Erythromycin	Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen	Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown.	30% increase
Flurazepam	Similar to diazepam.	Similar to diazepam.
Fluvoxamine	Similar to cimetidine.	Similar to cimetidine.
Halothane	Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.	Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A	Decreases theophylline clearance.	100% increase
Isoproterenol (IV)	Increases theophylline clearance.	20% decrease
Ketamine	Pharmacologic	May lower theophylline seizure threshold.
Lithium	Theophylline increases renal lithium clearance.	Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam	Similar to diazepam.	Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.	20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine	Similar to disulfiram.	80% increase
Midazolam	Similar to diazepam.	Similar to diazepam.
Moricizine	Increases theophylline clearance.	25% decrease
Pancuronium	Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition.	Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline	Decreases theophylline clearance.	30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.	25% decrease after two weeks of concurrent PB.
Phenytoin	Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.	Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone	Decreases theophylline clearance and pharmacologic interaction.	40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and pharmacologic interaction.	100% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin	Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.	20–40% decrease
Sulfinpyrazone	Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.	20% decrease
Tacrine	Similar to cimetidine, also increases renal clearance theophylline.	90% increase
Thiabendazole	Decreases theophylline clearance.	190% increase
Ticlopidine	Decreases theophylline clearance.	60% increase
Troleandomycin	Similar to erythromycin.	33–100% increase depending on troleandomycin dose.
Verapamil	Similar to disulfiram.	20% increase

Table name:

Interacting DrugInteracting Drug	InteractionInteraction
Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products.
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Factors	Dosage Adjustments for REXULTI (2.5)
Strong CYP2D6* or CYP3A4 inhibitors	Administer half of usual dose
Strong/moderate CYP2D6 with Strong/moderate CYP3A4 inhibitors	Administer a quarter of usual dose
Known CYP2D6 Poor Metabolizers taking strong/moderate CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double the usual dose and further adjust based on clinical response

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase ^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide ^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

Table name:

Table 3: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Indinavir (See PRECAUTIONS, Table 9 for Recommended Alterations in Dose or Regimen)
Coadministered drug	Dose of Coadministered drug (mg)	Dose of CRIXIVAN (mg)	n	Ratio (with/without CRIXIVAN) of Coadministered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00
				C_max	AUC	C_min
All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated.
Clarithromycin	500 twice daily, 7 days	800 three times daily, 7 days	12	1.19 (1.02, 1.39)	1.47 (1.30, 1.65)	1.97 (1.58, 2.46) n=11
Efavirenz	200 once daily, 14 days	800 three times daily, 14 days	20	No significant change	No significant change	--
Ethinyl Estradiol (ORTHO-NOVUM 1/35)Registered trademark of Ortho Pharmaceutical Corporation.	35 mcg, 8 days	800 three times daily, 8 days	18	1.02 (0.96, 1.09)	1.22 (1.15, 1.30)	1.37 (1.24, 1.51)
Isoniazid	300 once daily in the morning, 8 days	800 three times daily, 8 days	11	1.34 (1.12, 1.60)	1.12 (1.03, 1.22)	1.00 (0.92, 1.08)
MethadoneStudy conducted in subjects on methadone maintenance.	20-60 once daily in the morning, 8 days	800 three times daily, 8 days	12	0.93 (0.84, 1.03)	0.96 (0.86, 1.06)	1.06 (0.94, 1.19)
Norethindrone (ORTHO-NOVUM 1/35)	1 mcg, 8 days	800 three times daily, 8 days	18	1.05 (0.95, 1.16)	1.26 (1.20, 1.31)	1.44 (1.32, 1.57)
Rifabutin 150 mg once daily in the morning, 11 days + indinavir compared to 300 mg once daily in the morning, 11 days alone	150 once daily in the morning, 10 days 300 once daily in the morning, 10 days	800 three times daily, 10 days 800 three times daily, 10 days	14 10	1.29 (1.05, 1.59) 2.34 (1.64, 3.35)	1.54 (1.33, 1.79) 2.73 (1.99, 3.77)	1.99 (1.71, 2.31) n=13 3.44 (2.65, 4.46) n=9
Ritonavir	100 twice daily, 14 days	800 twice daily, 14 days	10, 4Parallel group design; n for coadministered drug + indinavir, n for coadministered drug alone.	1.61 (1.13, 2.29)	1.72 (1.20, 2.48)	1.62 (0.93, 2.85)
	200 twice daily, 14 days	800 twice daily, 14 days	9, 5	1.19 (0.85, 1.66)	1.96 (1.39, 2.76)	4.71 (2.66, 8.33) n=9, 4
Saquinavir
Hard gel formulation	600 single dose	800 three times daily, 2 days	6	4.7 (2.7, 8.1)	6.0 (4.0, 9.1)	2.9 (1.7, 4.7)C_6hr
Soft gel formulation	800 single dose	800 three times daily, 2 days	6	6.5 (4.7, 9.1)	7.2 (4.3, 11.9)	5.5 (2.2, 14.1)
Soft gel formulation	1200 single dose	800 three times daily, 2 days	6	4.0 (2.7, 5.9)	4.6 (3.2, 6.7)	5.5 (3.7, 8.3)
Sildenafil	25 single dose	800 three times daily	6	See text below for discussion of interaction.
StavudineStudy conducted in HIV-positive subjects.	40 twice daily, 7 days	800 three times daily, 7 days	13	0.86 (0.73, 1.03)	1.21 (1.09, 1.33)	Not Done
Theophylline	250 single dose (on Days 1 and 7)	800 three times daily, 6 days (Days 2 to 7)	12, 4	0.88 (0.76, 1.03)	1.14 (1.04, 1.24)	1.13 (0.86, 1.49) n=7, 3
Trimethoprim/ Sulfamethoxazole
Trimethoprim	800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days	400 q6h, 7 days	12	1.18 (1.05, 1.32)	1.18 (1.05, 1.33)	1.18 (1.00, 1.39)
Trimethoprim/ Sulfamethoxazole
Sulfamethoxazole	800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days	400 q6h, 7 days	12	1.01 (0.95, 1.08)	1.05 (1.01, 1.09)	1.05 (0.97, 1.14)
Vardenafil	10 single dose	800 three times daily	18	See text below for discussion of interaction.
Zidovudine	200 three times daily, 7 days	1000 three times daily, 7 days	12	0.89 (0.73, 1.09)	1.17 (1.07, 1.29)	1.51 (0.71, 3.20) n=4
Zidovudine/ Lamivudine
Zidovudine	200/150 three times daily, 7 days	800 three times daily, 7 days	6, 7	1.23 (0.74, 2.03)	1.39 (1.02, 1.89)	1.08 (0.77, 1.50) n=5, 5
Zidovudine/ Lamivudine
Lamivudine	200/150 three times daily, 7 days	800 three times daily, 7 days	6, 7	0.73 (0.52, 1.02)	0.91 (0.66, 1.26)	0.88 (0.59, 1.33)

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CONCOMITANT DRUG	CLINICAL EFFECT(S)
Amphetamines, cocaine, other sympathomimetic agents	Additive hypertension, tachycardia, possibly cardiotoxicity
Atropine, scopolamine, antihistamines, other anticholinergic agents	Additive or super-additive tachycardia, drowsiness
Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants	Additive tachycardia, hypertension, drowsiness
Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants	Additive drowsiness and CNS depression
Disulfiram	A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge
Fluoxetine	A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days
Antipyrine, barbiturates	Decreased clearance of these agents, presumably via competitive inhibition of metabolism
Theophylline	Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
↓=Decreased (induces lamotrigine glucuronidation). ↑=Increased (inhibits lamotrigine glucuronidation). ?=Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine (CBZ) and CBZ epoxide	? CBZ epoxide	May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T ₄ and T ₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT ₄. Continued administration results in a decrease in serum T ₄ and normal FT ₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T ₄ and T ₃ to TBG and transthyretin. An initial increase in serum FT ₄, is followed by return of FT ₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T ₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T ₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T ₄ to T ₃, leading to decreased T ₃ levels. However, serum T ₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T ₃ and T ₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T ₃ concentrations by 30% with minimal change in serum T ₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T ₃ and T ₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
↓= Decreased (induces lamotrigine gluronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
?= Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
	? CBZ epoxide	May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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edema
hereditary coumarin resistance
hyperlipemia

hypothyroidism
nephrotic syndrome

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Table 3Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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CONCOMITANT DRUG	CLINICAL EFFECT(S)
Amphetamines, cocaine, other sympathomimetic agents	Additive hypertension, tachycardia, possibly cardiotoxicity
Atropine, scopolamine, antihistamines, other anticholinergic agents	Additive or super-additive tachycardia, drowsiness
Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants	Additive tachycardia, hypertension, drowsiness
Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants	Additive drowsiness and CNS depression
Disulfiram	A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge
Fluoxetine	A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days
Antipyrine, barbiturates	Decreased clearance of these agents, presumably via competitive inhibition of metabolism
Theophylline	Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco
Opioids	Cross-tolerance and mutual potentiation
Naltrexone	Oral THC effects were enhanced by opioid receptor blockade.
Alcohol	Increase in the positive subjective mood effects of smoked marijuana

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir )	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 4: Clinically Relevant Interactions Affecting Omeprazole When Co-Administered with Other Drugs
CYP2C19 or CYP3A4 Inducers
Clinical Impact:	Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3) ].
Intervention:	St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions (5.9) ]. Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:	Increased exposure of omeprazole [see Clinical Pharmacology (12.3) ].
Intervention:	Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole.

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edema
hereditary coumarin resistance
hyperlipemia

hypothyroidism
nephrotic syndrome

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Table 5. Drugs That May Decrease Conversion of T4 to T3
Potential impact: Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased.
Drug or Drug Class	Effect
Beta-adrenergic antagonists (e.g., Propranolol > 160 mg/day)	In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change, TSH levels remain normal, and patients are clinically euthyroid. Actions of particular beta-adrenergic antagonists may be impaired when a hypothyroid patient is converted to the euthyroid state.
Glucocorticoids (e.g., Dexamethasone > 4 mg/day)	Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (See above).
Other drugs: Amiodarone	Amiodarone inhibits peripheral conversion of levothyroxine (T4) to triiodothyronine (T3) and may cause isolated biochemical changes (increase in serum free-T4, and decreased or normal free-T3) in clinically euthyroid patients.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Laboratory Tests	Effect of Salicylates
Thyroid Function	Decreased PBI; increased T₃ uptake
Urinary Sugar	False negative with glucose oxidase; false positive with Clinitest with high-dose salicylate therapy (2-5 g qd)
5 Hydroxyindole acetic acid	False negative with fluorometric test
Acetone, Ketone Bodies	False positive FeCl₃ in Gerhardt reaction; red color persists with boiling
17-OH corticosteroids	False reduced values with >4.8 g qd salicylate
Vanilmandelic Acid	False reduced values
Uric Acid	May increase or decrease depending on dose
Prothrombin	Decreased levels; slightly increased prothrombin time

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AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxideIs not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.6).]
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported . Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [see Adverse Reactions (6.1).]
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution 2-fold increase in exposure	Monitor for sildenafil toxicity (see Pharmacokinetics -(12.3)-] .
Duloxetine	Avoid Use 5-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx ^® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2)].	Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

Table name:

Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin dailyFor patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table II. Clinically significant drug interactions with theophylline*.
Drug	Type of Interaction	Effect**
* Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
** Average effect on steady state theophylline concentration or other clinical effect forpharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine	Theophylline blocks	Higher doses of adenosine
	adenosine receptors.	may be required to achieve
		desired effect.
Alcohol	A single large dose of alcohol	30% increase
	(3 ml/kg of whiskey) decreases
	theophylline clearance for up
	to 24 hours
Allopurinol	Decreases theophylline clearance	25% increase at allopurinol
	doses ≥600 mg/day.
Amino glutethimide	Increases theophylline clearance	25% decrease
	by induction of microsomal enzyme
	activity.
Carbamazepine	Similar to aminoglutethimide	30% decrease
Cimetidine	Decreases theophylline clearance	70% increase
	by inhibiting cytochrome P450 1A2.
Ciprofloxacin	Similar to cimetidine.	40% increase
Clarithromycin	Similar to erythromycin.	25% increase
Diazepam	Benzodiazepines increase CNS	Larger diazepam doses
	concentrations of adenosine, a potent	may be required to
	CNS depressant, while theophylline	produce desired level of
	blocks adenosine receptors.	sedation. Discontinuation
		of theophylline without
		reduction of diazepam
		dose may result in
		respiratory depression.
Disulfiram	Decreases theophylline clearance	50% increase
	by inhibiting hydroxylation and
	demethylation.
Enoxacin	Similar to cimetidine.	300% increase
Ephedrine	Synergistic CNS effects.	Increased frequency of
		nausea, nervousness,
		and insomnia.
Erythromycin	Erythromycin metabolite decreases	35% increase.
	theophylline clearance by inhibiting	Erythromycin steady-state
	cytochrome P450 3A3	serum concentrations
		decrease by a similar amount.
Estrogen	Estrogen containing oral contraceptives decrease theophylline	30% increase

	clearance in a dose-dependent fashion.
	The effect of progesterone on theophylline
	clearance is unknown.
Flurazepam	Similar to diazepam.	Similar to diazepam.
Fluvoxamine	Similar to cimetidine.	Similar to cimetidine.
Halothane	Halothane sensitizes the	Increased risk of ventricular
	myocardium to catecholamines,	arrhythmias
	theophylline increases release of
	endogenous catecholamines.
Interferon, human	Decreases theophylline clearance.	100% increase
recombinant alpha-A
Isoproterenol (IV)	Increases theophylline clearance.	20% decrease
Ketamine	Pharmacologic	May lower theophylline
		seizure threshold.
Lithium	Theophylline increases renal	Lithium dose required to
	lithium clearance.	achieve a therapeutic
		serum concentration
		increased an average of
		60%.
Lorazepam	Similar to diazepam.	Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.	20% increase after low dose
		MTX, higher dose MTX may
		have a greater effect.
Mexiletine	Similar to disulfiram.	80% increase
Midazolam	Similar to diazepam.	Similar to diazepam.
Moricizine	Increases theophylline clearance.	25% decrease
Pancuronium	Theophylline may antagonize	Larger dose of pancuronium may be required to
	non-depolarizing neuromuscular	Larger dose of pancuronium may be required to
	blocking effects; possibly due to	achieve neuromuscular
	phosphodiesterase inhibition.	blockade.
Pentoxifylline	Decreases theophylline clearance.	30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.	25% decrease after two
		weeks of concurrent PB.
Phenytoin	Phenytoin increases theophylline	Serum theophylline and
	clearance by increasing microsomal	phenytoin concentrations
	enzyme activity. Theophylline decreases phenytoin absorption.	decrease about 40%.

Propafenone	Decreases theophylline clearance	40% increase. Beta-2
	and pharmacologic interaction.	blocking effect may
		decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and	100% increase. Beta-2
	pharmacologic interaction.	blocking effect may
		decrease efficacy
		of theophylline.
Rifampin	Increases theophylline clearance	20-40% decrease
	by increasing cytochrome P450 1A2
	and 3A3 activity.
Sulfinpyrazone	Increases theophylline clearance by	20% decrease
	increasing demethylation and hydroxyllation.
	Decreases renal clearance of
	theophylline.
Tacrine	Similar to cimetidine, also increases	90% increase
	renal clearance of theophylline.
Thiabendazole	Decreases theophylline clearance.	190% increase
Ticlopidine	Decreases theophylline clearance.	60% increase
Troleandomycin	Similar to erythromycin.	33-100% increase depending
		on troleandomycin dose.
Verapamil	Similar to disulfiram.	20% increase

Table name:

Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin	Monitor phenytoin level (7)
Methotrexate	Monitor for methotrexate toxicity (7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)

Table name:

AED Co-administered	AED Concentration	TOPAMAX Concentration
NC = Less than 10% change in plasma concentration. NE = Not Evaluated
Phenytoin	NC or 25% increase = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide = Is not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Table 4. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug Name	Effect on Concentration of Ritonavir or Concomitant Drug	Clinical Comments
HIV-Antiviral Agents
HIV-1 Protease Inhibitor: atazanavir darunavir fosamprenavir	↑ amprenavir ↑ atazanavir ↑ darunavir	See the complete prescribing information for fosamprenavir, atazanavir, darunavir, for details on co-administration with ritonavir.
HIV-1 Protease Inhibitor: indinavir	↑ indinavir	Appropriate doses for this combination, with respect to efficacy and safety, have not been established.
HIV-1 Protease Inhibitor: saquinavir	↑ saquinavir	See the complete prescribing information for saquinavir for details on co-administration of saquinavir and ritonavir. Saquinavir/ritonavir in combination with rifampin is not recommended, due to the risk of severe hepatotoxicity (presenting as increased hepatic transaminases) if the three drugs are given together.
HIV-1 Protease Inhibitor: tipranavir	↑ tipranavir	See the complete prescribing information for tipranavir for details on co-administration of tipranavir and ritonavir.
Non-Nucleoside Reverse Transcriptase Inhibitor: delavirdine	↑ ritonavir	Appropriate doses of this combination with respect to safety and efficacy have not been established.
HIV-1 CCR5 – antagonist: maraviroc	↑ maraviroc	See the complete prescribing information for maraviroc for details on co-administration of maraviroc and ritonavir-containing protease inhibitors.
Integrase Inhibitor: raltegravir	↓ raltegravir	The effects of ritonavir on raltegravir with ritonavir dosage regimens greater than 100 mg twice daily have not been evaluated, however raltegravir concentrations may be decreased with ritonavir coadministration.
Other Agents
Analgesics, Narcotic: tramadol, propoxyphene, methadone, fentanyl	↑ analgesics ↓ methadone ↑ fentanyl	A dose decrease may be needed for these drugs when co-administered with ritonavir. Dosage increase of methadone may be considered. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with NORVIR.
Anesthetic: meperidine	↓ meperidine/ ↑ normeperidine (metabolite)	Dosage increase and long-term use of meperidine with ritonavir are not recommended due to the increased concentrations of the metabolite normeperidine which has both analgesic activity and CNS stimulant activity (e.g., seizures).
Antialcoholics: disulfiram/metronidazole		Ritonavir formulations contain ethanol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Antiarrhythmics: disopyramide, lidocaine, mexiletine	↑ antiarrhythmics	For contraindicated antiarrhythmics [see Contraindications (4)]. Caution is warranted and therapeutic concentration monitoring is recommended for antiarrhythmics when co-administered with ritonavir, if available.
Anticancer Agents: dasatinib, nilotinib, venetoclax, vincristine, vinblastine	↑ anticancer agents	For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when ritonavir is administered concurrently with vincristine or vinblastine. Clinicians should be aware that if the ritonavir containing regimen is withheld for a prolonged period, consideration should be given to altering the regimen to not include a CYP3A or P-gp inhibitor in order to control HIV-1 viral load.A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as NORVIR. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions. Coadministration of venetoclax and NORVIR may increase the risk of tumor lysis syndrome. Refer to the venetoclax prescribing information for dosing instructions.
Anticoagulant: warfarin	↑↓ warfarin	Initial frequent monitoring of the INR during ritonavir and warfarin co-administration is recommended.
Anticoagulant: rivaroxaban	↑ rivaroxaban	Avoid concomitant use of rivaroxaban and ritonavir. Co-administration of ritonavir and rivaroxaban may lead to risk of increased bleeding.
Anticonvulsants: carbamazepine, clonazepam, ethosuximide	↑ anticonvulsants	A dose decrease may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available.
Anticonvulsants: divalproex, lamotrigine, phenytoin	↓ anticonvulsants	A dose increase may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available.
Antidepressants: nefazodone, selective serotonin reuptake inhibitors (SSRIs): e.g. fluoxetine, paroxetine, tricyclics: e.g. amitriptyline, nortriptyline	↑ antidepressants	A dose decrease may be needed for these drugs when co-administered with ritonavir.
Antidepressant: bupropion	↓ bupropion ↓ active metabolite, hydroxybupropion	Patients receiving ritonavir and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant: desipramine	↑ desipramine	Dosage reduction and concentration monitoring of desipramine is recommended.
Antidepressant: trazodone	↑ trazodone	Adverse events of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and NORVIR. A lower dose of trazodone should be considered.
Antiemetic: dronabinol	↑ dronabinol	A dose decrease of dronabinol may be needed when co-administered with ritonavir.
Antifungal: ketoconazole itraconazole voriconazole	↑ ketoconazole ↑ itraconazole ↓ voriconazole	For contraindicated antifungals, [see Contraindications (4)]. High doses of ketoconazole or itraconazole (greater than 200 mg per day) are not recommended. Co-administration of voriconazole and ritonavir doses of 400 mg every 12 hours or greater is contraindicated [see Contraindications (4)]. Co-administration of voriconazole and ritonavir 100 mg should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.
Anti-gout: colchicine	↑ colchicine	Concomitant administration with colchicine is contraindicated in patients with renal and/or hepatic impairment [see Contraindications (4)]. For patients with normal renal or hepatic function: Treatment of gout flares-co-administration of colchicine in patients on ritonavir: 0.6 mg (one tablet) for one dose, followed by 0.3 mg (half tablet) one hour later. Dose to be repeated no earlier than three days. Prophylaxis of gout flares-co-administration of colchicine in patients on ritonavir: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on ritonavir: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Anti-infective: clarithromycin	↑ clarithromycin	For patients with renal impairment, adjust clarithromycin dose as follows: For patients with CL_CR 30 to 60 mL per min the dose of clarithromycin should be reduced by 50%. For patients with CL_CR less than 30 mL per min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary.
Antimycobacterial: bedaquiline	↑ bedaquiline	Bedaquiline should only be used with ritonavir if the benefit of co-administration outweighs the risk.
Antimycobacterial: rifabutin	↑ rifabutin and rifabutin metabolite	Dosage reduction of rifabutin by at least three-quarters of the usual dose of 300 mg per day is recommended (e.g., 150 mg every other day or three times a week). Further dosage reduction may be necessary.
Antimycobacterial: rifampin	↓ ritonavir	May lead to loss of virologic response. Alternate antimycobacterial agents such as rifabutin should be considered.
Antiparasitic: atovaquone	↓ atovaquone	Clinical significance is unknown; however, increase in atovaquone dose may be needed.
Antiparasitic: quinine	↑ quinine	A dose decrease of quinine may be needed when co-administered with ritonavir.
Antipsychotics: perphenazine, risperidone, thioridazine	↑ antipsychotics	For contraindicated antipsychotics, [see Contraindications (4)]. A dose decrease may be needed for these drugs when co-administered with ritonavir.
Antipsychotics: quetiapine	↑ quetiapine	Initiation of NORVIR in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking NORVIR: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
β-Blockers: metoprolol, timolol	↑ beta-blockers	Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with ritonavir.
Bronchodilator: theophylline	↓ theophylline	Increased dosage of theophylline may be required; therapeutic monitoring should be considered.
Calcium channel blockers: diltiazem, nifedipine, verapamil	↑ calcium channel blockers	Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with ritonavir.
Digoxin	↑ digoxin	Concomitant administration of ritonavir with digoxin may increase digoxin levels. Caution should be exercised when co-administering ritonavir with digoxin, with appropriate monitoring of serum digoxin levels.
Endothelin receptor antagonists: bosentan	↑ bosentan	Co-administration of bosentan in patients on ritonavir: In patients who have been receiving ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Co-administration of ritonavir in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of ritonavir. After at least 10 days following the initiation of ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Hepatitis C direct acting antiviral: simeprevir	↑simeprevir	It is not recommended to co-administer ritonavir with simeprevir.
HMG-CoA Reductase Inhibitor: atorvastatin rosuvastatin	↑ atorvastatin ↑ rosuvastatin	For contraindicated HMG-CoA Reductase inhibitors, [see Contraindications (4)]. Titrate atorvastatin and rosuvastatin dose carefully and use the lowest necessary dose. If NORVIR is used with another protease inhibitor, see the complete prescribing information for the concomitant protease inhibitor for details on co-administration with atorvastatin and rosuvastatin.
Immunosuppressants: cyclosporine, tacrolimus, sirolimus (rapamycin)	↑ immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with ritonavir.
Systemic/Inhaled/ Nasal/Ophthalmic Corticosteroids: e.g., betamethasone budesonide ciclesonide dexamethasone fluticasone methylprednisolone mometasone prednisone triamcinolone	↑ glucocorticoids	Coadministration with corticosteroids whose exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression. Alternative corticosteroids including beclomethasone and prednisolone (whose PK and/or PD are less affected by strong CYP3A inhibitors relative to other studied steroids) should be considered, particularly for long-term use.
Long-acting beta-adrenoceptor agonist: salmeterol	↑ salmeterol	Concurrent administration of salmeterol and ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Oral Contraceptives or Patch Contraceptives: ethinyl estradiol	↓ ethinyl estradiol	Alternate methods of contraception should be considered.
PDE5 Inhibitors: avanafil sildenafil, tadalafil, vardenafil	↑ avanafil ↑ sildenafil ↑ tadalafil ↑ vardenafil	For contraindicated PDE5 inhibitors, [see Contraindications (4)]. Do not use ritonavir with avanafil because a safe and effective avanafil dosage regimen has not been established. Particular caution should be used when prescribing sildenafil, tadalafil or vardenafil in patients receiving ritonavir. Coadministration of ritonavir with these drugs may result in an increase in PDE5 inhibitor associated adverse events, including hypotension, syncope, visual changes, and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio^®) is contraindicated [see Contraindications (4)]. The following dose adjustments are recommended for use of tadalafil (Adcirca^®) with ritonavir: Co-administration of ADCIRCA in patients on ritonavir: In patients receiving ritonavir for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Co-administration of ritonavir in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of ritonavir. Stop ADCIRCA at least 24 hours prior to starting ritonavir. After at least one week following the initiation of ritonavir, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for the treatment of erectile dysfunction: It is recommended not to exceed the following doses: Sildenafil: 25 mg every 48 hours Tadalafil: 10 mg every 72 hours Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events.
Sedative/hypnotics: buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem	↑ sedative/hypnotics	A dose decrease may be needed for these drugs when co-administered with ritonavir.
Sedative/hypnotics: Parenteral midazolam	↑ midazolam	For contraindicated sedative/hypnotics, [see Contraindications (4) ]. Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.
Stimulant: methamphetamine	↑ methamphetamine	Use with caution. A dose decrease of methamphetamine may be needed when co-administered with ritonavir.

Table name: Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.During concomitant use of diclofenac sodium delayed-release tablets and ACE-inhibitors, ARBs, or beta- blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of diclofenac sodium delayed-release tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS: Renal Toxicity and Hyperkalemia ). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.

Table 2. Clinically Significant Drug Interactions with Diclofenac
Drugs That Interfere with Hemostasis
Clinical Impact:
Intervention:	Monitor patients with concomitant use of diclofenac sodium delayed-release tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS: Hematologic Toxicity ).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ).
Intervention:	Concomitant use of diclofenac sodium delayed-release tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS: Hematologic Toxicity ). Diclofenac sodium delayed-release tablets are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:
Intervention:
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS: Renal Toxicity and Hyperkalemia ).
Digoxin
Clinical Impact:	The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of diclofenac sodium delayed-release tablets and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ).
Intervention:	The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of diclofenac sodium delayed-release tablets and pemetrexed may increase the risk of pemetrexed‑ associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of diclofenac sodium delayed-release tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or Inducers:
Clinical Impact:	Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Co-administration of diclofenac with CYP2C9 inhibitors (e.g. voriconazole) may enhance the exposure and toxicity of diclofenac whereas co‑administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of diclofenac.
Intervention:	A dosage adjustment may be warranted when diclofenac is administered with CYP2C9 inhibitors or inducers (see CLINICAL PHARMACOLOGY: Pharmacokinetics ).

Table name:

Table 7: Summary of AED Interactions with Oxcarbazepine
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400 to 2000	900	ncnc denotes a mean change of less than 10%	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100 to 150	600 to 1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250 to 500	600 to 1800 >1200 to 2400	nc ^, Pediatrics up to 40% increaseMean increase in adults at high oxcarbazepine doses [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400 to 2800	600 to 1800	nc	18% decrease [CI: 13% decrease, 40% decrease]

Table name:

Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Amiodarone, verapamil, diltiazem	Do not exceed 10 mg simvastatin daily
Amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

Table name:

AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide Is not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

Table name:

Table 13 Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
↓ = Decreased (induces lamotrigine glucuronidation) ↑ = Increased (inhibits lamotrigine glucuronidation) ? = Conflicting data
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine concentrations approximately 50%
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%
Carbamazepine and Carbamazepine epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%
	? Carbamazepine epoxide	May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold
	? valproate	There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

Table name:

AED Co-administered	AED Concentration	Topiramate Concentration
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
Phenytoin	NC or 25% increase= Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide= Is not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

Table name:

Table 8. Effect of Voriconazole on Pharmacokinetics of Other Drugs
[see Clinical Pharmacology (12.3) ]
Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C_max and AUC_τ)	Recommendations for Drug Dosage Adjustment/Comments
Sirolimus* (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin* (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz** (CYP3A4 Inhibition)	Significantly Increased	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg every 12h and efavirenz should be decreased to 300 mg every 24h
High-dose Ritonavir (400 mg every 12h) (CYP3A4 Inhibition) Low-dose Ritonavir (100 mg every 12h)	No Significant Effect of Voriconazole on Ritonavir C_max or AUC_τ Slight Decrease in Ritonavir C_max and AUC_τ	Contraindicated because of significant reduction of voriconazole C_max and AUC_τ Coadministration of voriconazole and low-dose ritonavir (100 mg every 12h) should be avoided (due to the reduction in voriconazole C_max and AUC_τ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Contraindicated
Cyclosporine* (CYP3A4 Inhibition)	AUC_τ Significantly Increased; No Significant Effect on C_max	When initiating therapy with Voriconazole for Injection in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When Voriconazole for Injection is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
Methadone*** (CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with Voriconazole for Injection. Extended and frequent monitoring for opiate-associated adverse events may be necessary [ see Drug Interactions (7) ]
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with Voriconazole for Injection. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [ see Drug Interactions (7) ].
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with Voriconazole for Injection. Extended and frequent monitoring for opiate-associated adverse events may be necessary [ see Drug Interactions (7) ].
NSAIDs**** including ibuprofen and diclofenac (CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [ see Drug Interactions (7) ].
Tacrolimus* (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with Voriconazole for Injection in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When Voriconazole for Injection is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin* (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)**	Increased	Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin* (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole* (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with Voriconazole for Injection in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects on Indinavir Exposure In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	No dosage adjustment for indinavir when coadministered with Voriconazole for Injection Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIs***** (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro , but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.
* Results based on in vivo clinical studies generally following repeat oral dosing with 200 mg twice daily voriconazole to healthy subjects Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12h for 1 day, then 200 mg every 12h for at least 2 days voriconazole to healthy subjects * Results based on in vivo clinical study following repeat oral dosing with 400 mg every 12h for 1 day, then 200 mg every 12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30 to 100 mg daily) ** Non-Steroidal Anti-Inflammatory Drug *** Non-Nucleoside Reverse Transcriptase Inhibitors

Table name:

Drugs that Affect Renal Function	A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrhythmics	Dofetilide	Concomitant administration with digoxin was associated with a higher rate of torsades de pointes.
	Sotalol	Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
	Dronedarone	Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog	Teriparatide	Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement	Thyroid	Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics	Epinephrine Norepinephrine Dopamine	Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents	Succinylcholine	May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements	Calcium	If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers		Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.

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Table 4 Other Potentially Significant Drug Interactions
Concomitant Drug Class or Food	Noted or anticipated Outcome	Clinical Comment
HMG-Co A Reductase Inhibitors: atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin	Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality)	Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy.
Other Lipid Lowering Drugs: fibrates, gemfibrozil
Digitalis Glycosides: digoxin	P-gp substrate; rhabdomyolysis has been reported

Table name:

Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

Table name:

CONCOMITANT DRUG	CLINICAL EFFECT(S)
Amphetamines, cocaine, other sympathomimetic agents	Additive hypertension, tachycardia, possibly cardiotoxicity
Atropine, scopolamine, antihistamines, other anticholinergic agents	Additive or super-additive tachycardia, drowsiness
Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants	Additive tachycardia, hypertension, drowsiness
Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants	Additive drowsiness and CNS depression
Disulfiram	A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge
Fluoxetine	A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days
Antipyrine, barbiturates	Decreased clearance of these agents,presumably via competitive inhibition of metabolism
Theophylline	Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco

Table name:

Table 3Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

Table name:

Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
Lopinavir plus ritonavir	Use lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

Table name:

Table 2: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 5 mg in BPH patients on stable alpha-blocker therapy (Study 1)
Alpha-Blocker		Simultaneous dosing of Vardenafil 5 mg and Alpha-Blocker, Placebo-Subtracted	Dosing of Vardenafil 5 mg and Alpha-Blocker Separated by 6 Hours, Placebo-Subtracted
Terazosin 5 or 10 mg daily	Standing SBP	-3 (-6.7, 0.1)	-4 (-7.4, -0.5)
Terazosin 5 or 10 mg daily	Supine SBP	-4 (-6.7, -0.5)	-4 (-7.1, -0.7)
Tamsulosin 0.4 mg daily	Standing SBP Supine SBP	-6 (-9.9, -2.1) -4 (-7.0, -0.8)	-4 (-8.3, -0.5) -5 (-7.9, -1.7)

Table name:

NA = Not available/reported
Digoxin concentrations increased greater than 50%
	Digoxin Serum Concentration Increase	Digoxin AUC Increase	Recommendations
Amiodarone	70%	NA	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
Captopril	58%	39%
Clarithromycin	NA	70%
Dronedarone	NA	150%
Gentamicin	129-212%	NA
Erythromycin	100%	NA
Itraconazole	80%	NA
Lapatinib	NA	180%
Nitrendipine	57%	15%
Propafenone	NA	60-270%
Quinidine	100%	NA
Ranolazine	50%	NA
Ritonavir	NA	86%
Telaprevir	50%	85%
Tetracycline	100%	NA
Verapamil	50-75%	NA
Digoxin concentrations increased less than 50%
Atorvastatin	22%	15%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
Carvedilol	16%	14%
Conivaptan	33%	43%
Diltiazem	20%	NA
Indomethacin	40%	NA
Nefazodone	27%	15%
Nifedipine	45%	NA
Propantheline	24%	24%
Quinine	NA	33%
Rabeprazole	29%	19%
Saquinavir	27%	49%
Spironolactone	25%	NA
Telmisartan	20-49%	NA
Ticagrelor	31%	28%
Tolvaptan	30%	20%
Trimethoprim	22-28%	NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate and sulfasalazine			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20-40% as necessary.

Table name:

Drugs That Interfere with Hemostasis
Clinical Impact:	Indomethacin and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of indomethacin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions ( 5.11 )].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions ( 5.2 ) ].
Intervention:	Concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions ( 5.11 )].Indomethacin is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of indomethacin capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.During concomitant use of indomethacin capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions ( 5.6 )].When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.It has been reported that the addition of triamterene to a maintenance schedule of Indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together.Both indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently [ see Warnings and Precautions ( 5.6 )].
Intervention:	Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels. [ see Warnings and Precautions ( 5.6 )].
Digoxin
Clinical Impact:	The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine's nephrotoxicity.
Intervention:	During concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions ( 5.2 )]. Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin [see Clinical Pharmacology ( 12.3 )].In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage.
Intervention:	The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity.NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed.In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Probenecid
Clinical Impact:	When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased.
Intervention:	During the concomitant use of indomethacin and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments.

Table name:

Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin dailyFor patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

Table name:

Drugs That Are Affected By Clarithromycin
Drug(s) with Pharmacokinetics Affected by Clarithromycin	Recommendation	Comments
Antiarrhythmics: Disopyramide Quinidine Dofetilide Amiodarone Sotalol Procainamide Digoxin	Not Recommended Use With Caution	Disopyramide, Quinidine: There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs [see Warnings and Precautions (5.3)]. Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine. There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide. Digoxin: Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are co-administered, inhibition of Pgp by clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range.
Oral Anticoagulants: Warfarin	Use With Caution	Oral anticoagulants: Spontaneous reports in the postmarketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously [see Warnings and Precautions (5.4)].
Antiepileptics: Carbamazepine	Use With Caution	Carbamazepine: Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered. Increased serum concentrations of carbamazepine were observed in clinical trials with clarithromycin. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with carbamazepine.
Antifungals: Itraconazole Fluconazole	Use With Caution No Dose Adjustment	Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly (see also Itraconazole under “Drugs That Affect Clarithromycin” in the table below). Clarithromycin may increase the plasma concentrations of itraconazole. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions. Fluconazole: [see Pharmacokinetics (12.3)]
Anti-Gout Agents: Colchicine (in patients with renal or hepatic impairment) Colchicine (in patients with normal renal and hepatic function)	Contraindicated Use With Caution	Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. The dose of colchicine should be reduced when co-administered with clarithromycin in patients with normal renal and hepatic function [see Contraindications (4.4) and Warnings and Precautions (5.4)].
Antipsychotics: Pimozide Quetiapine	Contraindicated	Pimozide: [See Contraindications (4.2)] Quetiapine: Quetiapine is a substrate for CYP3A4, which is inhibited by clarithromycin. Co-administration with clarithromycin could result in increased quetiapine exposure and possible quetiapine related toxicities. There have been postmarketing reports of somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation during concomitant administration. Refer to quetiapine prescribing information for recommendations on dose reduction if co-administered with CYP3A4 inhibitors such as clarithromycin.
Antispasmodics: Tolterodine (patients deficient in CYP2D6 activity)	Use With Caution	Tolterodine: The primary route of metabolism for tolterodine is via. CYP2D6. However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via. CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when co-administered with clarithromycin.
Antivirals: Atazanavir Saquinavir (in patients with decreased renal function) Ritonavir Etravirine Maraviroc Boceprevir (in patients with normal renal function) Didanosine Zidovudine	Use With Caution No Dose Adjustment	Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)]. Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction (see Saquinavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)]. Ritonavir, Etravirine: (see Ritonavir and Etravirine under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)]. Maraviroc: Clarithromycin may result in increases in maraviroc exposures by inhibition of CYP3A metabolism. See Selzentry^® prescribing information for dose recommendation when given with strong CYP3A inhibitors such as clarithromycin. Boceprevir: Both clarithromycin and boceprevir are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when co-administered. No dose adjustments are necessary for patients with normal renal function (see Victrelis^® prescribing information). Zidovudine: Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Administration of clarithromycin and zidovudine should be separated by at least two hours [see Pharmacokinetics (12.3)].
Calcium Channel Blockers: Verapamil Amlodipine Diltiazem Nifedipine	Use With Caution	Verapamil: Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, [see Warnings and Precautions (5.4)]. Amlodipine, Diltiazem: [See Warnings and Precautions (5.4)] Nifedipine: Nifedipine is a substrate for CYP3A. Clarithromycin and other macrolides are known to inhibit CYP3A. There is potential of CYP3A-mediated interaction between nifedipine and clarithromycin. Hypotension and peripheral edema were observed when clarithromycin was taken concomitantly with nifedipine [see Warnings and Precautions (5.4)].
Ergot Alkaloids: Ergotamine Dihydroergotamine	Contraindicated	Ergotamine, Dihydroergotamine: Postmarketing reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4.6)].
Gastroprokinetic Agents: Cisapride	Contraindicated	Cisapride: [See Contraindications (4.2)]
HMG-CoA Reductase Inhibitors: Lovastatin Simvastatin Atorvastatin Pravastatin Fluvastatin	Contraindicated Use With Caution No Dose Adjustment	Lovastatin, Simvastatin, Atorvastatin, Pravastatin, Fluvastatin: [See Contraindications (4.5) and Warnings and Precautions (5.4)]
Hypoglycemic Agents: Nateglinide Pioglitazone Repaglinide Rosiglitazone Insulin	Use With Caution	Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)] Insulin: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]
Immunosuppressants: Cyclosporine Tacrolimus	Use With Caution	Cyclosporine: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine. Tacrolimus: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with tacrolimus.
Phosphodiesterase inhibitors: Sildenafil Tadalafil Vardenafil	Use With Caution	Sildenafil, Tadalafil, Vardenafil: Each of these phosphodiesterase inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant administration of clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil, or vardenafil will result in increased exposure of these phosphodiesterase inhibitors. Co-administration of these phosphodiesterase inhibitors with clarithromycin is not recommended. Increased systemic exposure of these drugs may occur with clarithromycin; reduction of dosage for phosphodiesterase inhibitors should be considered (see their respective prescribing information).
Proton Pump Inhibitors: Omeprazole	No Dose Adjustment	Omeprazole: The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when coadministered with clarithromycin as a result of increased omeprazole exposures [see Pharmacokinetics (12.3)] (see also Omeprazole under “Drugs That Affect Clarithromycin” in the table below).
Xanthine Derivatives: Theophylline	Use With Caution	Theophylline: Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations [see Pharmacokinetics (12.3)]. Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range.
Triazolobenzodiazepines and Other Related Benzodiazepines: Midazolam Alprazolam Triazolam Temazepam Nitrazepam Lorazepam	Use With Caution No Dose Adjustment	Midazolam: When oral midazolam is co-administered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated [see Warnings and Precautions (5.4) and Pharmacokinetics (12.3)]. Triazolam, Alprazolam: Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is co-administered with clarithromycin. There have been postmarketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested. In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines. Temazepam, Nitrazepam, Lorazepam: For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.
Cytochrome P450 Inducers: Rifabutin	Use With Caution	Rifabutin: Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis (see Rifabutin under “Drugs That Affect Clarithromycin” in the table below).
Other Drugs Metabolized by CYP3A: Alfentanil Bromocriptine Cilostazol Methylprednisole Vinblastine Phenobarbital St. John’s Wort	Use With Caution	There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort.
Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A: Hexobarbital Phenytoin Valproate	Use With Caution	There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.
Drugs that Affect Clarithromycin
Drug(s) that Affect the Pharmacokinetics of Clarithromycin	Recommendation	Comments
Antifungals: Itraconazole	Use With Caution	Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions (see also Itraconazole under “Drugs That Are Affected By Clarithromycin” in the table above).
Antivirals: Atazanavir Ritonavir (in patients with decreased renal function) Saquinavir (in patients with decreased renal function) Etravirine Saquinavir (in patients with normal renal function) Ritonavir (in patients with normal renal function)	Use With Caution No Dose Adjustment	Atazanavir: When clarithromycin is co-administered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology (12.3)]. Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors. Ritonavir: Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with ritonavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium [see Pharmacokinetics (12.3)]. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors. Saquinavir: When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (refer to ritonavir above) [see Pharmacokinetics (12.3)]. Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.
Proton Pump Inhibitors: Omeprazole	Use With Caution	Omeprazole: Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole [see Pharmacokinetics (12.3)].
Miscellaneous Cytochrome P450 Inducers: Efavirenz Nevirapine Rifampicin Rifabutin Rifapentine	Use With Caution	Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are Affected By Clarithromycin” in the table above).

Table 3: Clinically Relevant Interactions Affecting Drugs Co-Administered with Omeprazole and Interaction with Diagnostics
Antiretrovirals
Clinical Impact:	The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
Intervention:	Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications (4)]. Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:	Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention:	Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact:	Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].
Intervention:	A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact:	Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)]. There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention:	Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6)].
Citalopram
Clinical Impact:	Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention:	Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:	Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].
Intervention:	Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:	Potential for increased exposure of phenytoin.
Intervention:	Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:	Increased exposure of diazepam [see Clinical Pharmacology (12.3)].
Intervention:	Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:	Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention:	Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:	Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:	Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)]. See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:	Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:	See Contraindications, Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact:	Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention:	Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:	Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10), Clinical Pharmacology (12.2)].
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:	Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact:	There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:	An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:	There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:	Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.

Table name:

Table 3Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

Table name:

Table 5. Clinically-Significant Drug Interactions with Sertraline Hydrochloride
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	The concomitant use of SSRIs including sertraline hydrochloride and MAOIs increases the risk of serotonin syndrome.
Intervention:	Sertraline hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [See Dosage and Administration (2.5), Contraindications (4), Warnings and Precautions (5.2)].
Examples:	selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
Pimozide
Clinical Impact:	Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QT prolongation and ventricular arrhythmias.
Intervention:	Concomitant use of pimozide and sertraline hydrochloride is contraindicated [See Contraindications (4)].
Other Serotonergic Drugs
Clinical Impact:	The concomitant use of serotonergic drugs with sertraline hydrochloride increases the risk of serotonin syndrome.
Intervention:	Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of sertraline hydrochloride and/or concomitant serotonergic drugs [See Warnings and Precautions (5.2)].
Examples:	other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort
Drugs that Interfere with Hemostasis (antiplatelet agents and anticoagulants)
Clinical Impact:	The concurrent use of an antiplatelet agent or anticoagulant with sertraline hydrochloride may potentiate the risk of bleeding.
Intervention:	Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [See Warnings and Precautions (5.3)].
Examples:	aspirin, clopidogrel, heparin, warfarin
Drugs Highly Bound to Plasma Protein
Clinical Impact:	Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of sertraline hydrochloride with another drug that is highly bound to plasma protein may increase free concentrations of sertraline hydrochloride or other tightly-bound drugs in plasma [See Clinical Pharmacology (12.3)].
Intervention:	Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs as warranted.
Examples:	warfarin
Drugs Metabolized by CYP2D6
Clinical Impact:	Sertraline hydrochloride is a CYP2D6 inhibitor [See Clinical Pharmacology (12.3)]. The concomitant use of sertraline hydrochloride with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate.
Intervention:	Decrease the dosage of a CYP2D6 substrate if needed with concomitant sertraline hydrochloride use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride is discontinued.
Examples:	propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine
Phenytoin
Clinical Impact:	Phenytoin is a narrow therapeutic index drug. Sertraline hydrochloride may increase phenytoin concentrations.
Intervention:	Monitor phenytoin levels when initiating or titrating sertraline hydrochloride. Reduce phenytoin dosage if needed.
Examples:	phenytoin, fosphenytoin

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄ . Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³ I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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AED Co - administered	AED Concentration	Topiramate Concentration
Phenytoin	NCor25%increase ^a	48%decrease
Carbamazepine(CBZ)	NC	40%decrease
CBZepoxide ^b	NC	NE
Valproic acid	11%decrease	14%decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NCatTPM dosesupto400 mg/day	13%decrease

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet is taken within 2 hours of these products (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir )	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)	Do not exceed 40 mg atorvastatin daily

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Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen is not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxenis not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:	Patients simultaneously receiving naproxen and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
↓= Decreased (induces lamotrigine glucuronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ? = Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine concentrations approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine and carbamazepine epoxide	? carbamazepine epoxide	May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide Is not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.12, 7.3)

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Table II. Clinically significant drug interactions with theophylline*.
Drug	Type of Interaction	Effect†
* Refer to PRECAUTIONS, Drug Interactions for further information regarding table. † Average effect on steady state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine	Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.
Alcohol	A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours.	30% increase
Allopurinol	Decreases theophylline clearance at allopurinol doses ≥600 mg/day.	25% increase
Aminoglutethimide	Increases theophylline clearance by induction of microsomal enzyme activity.	25% decrease
Carbamazepine	Similar to aminoglutethimide.	30% decrease
Cimetidine	Decreases theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase
Ciprofloxacin	Similar to cimetidine.	40% increase
Clarithromycin	Similar to erythromycin.	25% increase
Diazepam	Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.	Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram	Decreases theophylline clearance by inhibiting hydroxylation and demethylation.	50% increase
Enoxacin	Similar to cimetidine.	300% increase
Ephedrine	Synergistic CNS effects.	Increased frequency of nausea, nervousness, and insomnia.
Erythromycin	Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen	Estrogen containing oral contraceptives decrease theophylline clearance in a dose- dependent fashion. The effect of progesterone on theophylline clearance is unknown.	30% increase
Flurazepam	Similar to diazepam.	Similar to diazepam.
Fluvoxamine	Similar to cimetidine.	Similar to cimetidine
Halothane	Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.	Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A	Decreases theophylline clearance.	100% increase
Isoproterenol (IV)	Increases theophylline clearance.	20% decrease
Ketamine	Pharmacologic.	May lower theophylline seizure threshold.
Lithium	Theophylline increases renal lithium clearance.	Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam	Similar to diazepam.	Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.	20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine	Similar to disulfiram.	80% increase
Midazolam	Similar to diazepam.	Similar to diazepam.
Moricizine	Increases theophylline clearance.	25% decrease
Pancuronium	Theophylline may antagonize non-depolarizing neuromuscular blocking effects, possibly due to phosphodiesterase inhibition.	Larger dose of pancuronium may be required to achieve neuromuscular blockade
Pentoxifylline	Decreases theophylline clearance.	30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.	25% decrease after two weeks of concurrent PB.
Phenytoin	Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption.	Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone	Decreases theophylline clearance and pharmacologic interaction.	40% increase. Beta₂ blocking effect may decrease efficacy of theophylline
Propranolol	Similar to cimetidine and pharmacologic interaction.	100% increase. Beta₂ blocking effect may decrease efficacy of theophylline
Rifampin	Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.	20-40% decrease
St. John's Wort (Hypericum Perforatum)	Decrease in theophylline plasma concentrations.	Higher doses of theophylline may be required to achieve desired effect. Stopping St. John's Wort may result in theophylline toxicity.
Sulfinpyrazone	Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.	20% decrease
Tacrine	Similar to cimetidine, also increases renal clearance of theophylline.	90% increase
Thiabendazole	Decreases theophylline clearance.	190% increase
Ticlopidine	Decreases theophylline clearance.	60% increase
Troleandomycin	Similar to erythromycin.	33-100% increase depending on troleandomycin dose.
Verapamil	Similar to disulfiram.	20% increase

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Table 2: Rifabutin Interaction Studies
↑ indicates increase; ↓ indicates decrease; ↔ indicates no significant change
QD-once daily; BID-twice daily; TID – thrice daily
ND -No Data
AUC -Area under the Concentration vs. Time Curve; C_m _a _x -Maximum serum concentration
^a compared to rifabutin 300 mg QD alone
^b compared to historical control (fosamprenavir/ritonavir 700/100 mg BID)
^c also taking zidovudine 500 mg QD
^d compared to rifabutin 150 mg QD alone
^e compared to rifabutin 300 mg QD alone
^f data from a case report
^g compared to voriconazole 200 mg BID alone
Coadministered drug	Dosing regimen of coadministered drug	Dosing regimen of rifabutin	Study population ( n )	Effect on rifabutin	Effect on coadministered drug	Recommendation
ANTIVIRALS
Amprenavir	1200 mg BID x 10 days	300 mg QD x 10 days	Healthy male subjects (6)	↑ AUC by 193%, ↑ C_m _a _x by 119%	↔	Reduce rifabutin dose by at least 50%. Monitor closely for adverse reactions.
Delavirdine	400 mg TID	300 mg QD	HIV-infected patients (7)	↑ AUC by 230%, ↑ C_m _a _x by 128%	↓ AUC by 80%, ↓ Cmax by 75%, ↓ C_m _i _n by 17%	CONTRAINDICATED
Didanosine	167 or 250 mg BID x 12 days	300 or 600 mg QD x 1	HIV-infected patients (11)	↔	↔
Fosamprenavir/ ritonavir	700 mg BID plus ritonavir 100 mg BID x 2 weeks	150 mg every other day x 2 weeks	Healthy subjects (15)	↔ AUC^a ↓ C_m _a _x by 15%	↑ AUC by 35%^b, ↑ C_m _a _x by 36%, ↑ C_m _i _n by 36%	Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with fosamprenavir/ritonavir combination.
Indinavir	800 mg TID x 10 days	300 mg QD x 10 days	Healthy subjects (10)	↑ AUC by 173%, ↑ Cmax by 134%	↓ AUC by 34%, ↓ C_m _a _x by 25%, ↓ C_m _i _n by 39%	Reduce rifabutin dose by 50%, and increase indinavir dose from 800 mg to 1000 mg TID.
Lopinavir/ ritonavir	400/100 mg BID x 20 days	150 mg QD x 10 days	Healthy subjects (14)	↑ AUC by 203%^c ↓ C_m _a _x by 112%	↔	Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed.
Saquinavir/ ritonavir	1000/100 mg BID x 14 or 22 days	150 mg every 3 days X 21 to 22 days	Healthy subjects	↑ AUC by 53% ^d ↑ C_m _a _x by 88% (n=11)	↓ AUC by 13%, ↓ C_m _a _x by 15%, (n=19)	Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with saquinavir/ritonavir combination. Monitor closely for adverse reactions.
Ritonavir	500 mg BID x 10 days	150 mg QD x 16 days	Healthy subjects (5)	↑ AUC by 300%, ↑ C_m _a _x by 150%	ND	Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with lopinavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed.
Tipranavir/ ritonavir	500/200 BID X 15 doses	150 mg single dose	Healthy subjects (20)	↑ AUC by 190%, ↑ C_m _a _x by 70%	↔	Reduce rifabutin dose by at least 75% (to a maximum 150 mg every other day or three times per week) when given with tipranavir/ritonavir combination. Monitor closely for adverse reactions. Reduce rifabutin dosage further, as needed.
Nelfinavir	1250 mg BID x 7 to 8 days	150 mg QD x 8 days	HIV-infected patients (11)	↑ AUC by 83%,^e ↑ C_m _a _x by 19%	↔	Reduce rifabutin dose by 50% (to 150 mg QD) and increase the nelfinavir dose to 1250 mg BID
Zidovudine	100 or 200 mg q4h	300 or 450 mg QD	HIV-infected patients (16)	↔	↓ AUC by 32%, ↓ C_m _a _x by 48%	Because zidovudine levels remained within the therapeutic range during coadministration of rifabutin, dosage adjustments are not necessary.
ANTIFUNGALS
Fluconazole	200 mg QD x 2 weeks	300 mg QD x 2 weeks	HIV-infected patients (12)	↑ AUC by 82%, ↑ C_m _a _x by 88%	↔	Monitor for rifabutin associated adverse events. Reduce rifabutin dose or suspend rifabutin use if toxicity is suspected.
Posaconazole	200 mg QD x 10 days	300 mg QD x 17 days	Healthy subjects (8)	↑ AUC by 72%, ↑ C_m _a _x by 31%	↓ AUC by 49%, ↓ C_m _a _x by 43%	If co-administration of these two drugs cannot be avoided, patients should be monitored for adverse events associated with rifabutin administration, and lack of posaconazole efficacy.
Itraconazole	200 mg QD	300 mg QD	HIV-Infected patients (6)	↑^f	↓ AUC by 70%, ↓ C_m _a _x by 75%	If co-administration of these two drugs cannot be avoided, patients should be monitored for adverse events associated with rifabutin administration, and lack of itraconazole efficacy. In a separate study, one case of uveitis was associated with increased serum rifabutin levels following coadministration of rifabutin (300 mg QD) with itraconazole (600 to 900 mg QD).
Voriconazole	400 mg BID x 7 days (maintenance dose)	300 mg QD x 7 days	Healthy male subjects (12)	↑ AUC by 331%, ↑ C_m _a _x by 195%	↑ AUC by ~100%, ↑ C_m _a _x by ~100%^g	CONTRAINDICATED
ANTI - PCP ( Pneumocystis carinii pneumonia )
Dapsone	50 mg QD	300 mg QD	HIV-infected patients (16)	ND	↓ AUC by 27 to 40%
Sulfamethoxazole-Trimethoprim	800/160 mg	300 mg QD	HIV-infected patients (12)	↔	↓ AUC by 15 to 20%
ANTI - MAC ( Mycobacterium avium intracellulare complex )
Azithromycin	500 mg QD x 1 day, then 250 mg QD x 9 days	300 mg QD	Healthy subjects (6)	↔	↔
Clarithromycin	500 mg BID	300 mg QD	HIV-infected patients (12)	↑ AUC by 75%	↓ AUC by 50%	Monitor for rifabutin associated adverse events. Reduce dose or suspend use of rifabutin if toxicity is suspected. Alternative treatment for clarithromycin should be considered when treating patients receiving rifabutin
ANTI - TB ( Tuberculosis )
Ethambutol	1200 mg	300 mg QD X 7 days	Healthy subjects (10)	ND	↔
Isoniazid	300 mg	300 mg QD X 7 days	Healthy subjects (6)	ND	↔
OTHER
Methadone	20 to 100 mg QD	300 mg QD X 13 days	HIV-infected patients (24)	ND	↔
Ethinylestradiol (EE)/ Norethindrone (NE)	35 mg EE / 1 mg NE X 21 days	300 mg QD X 10 days	Healthy female subjects (22)	ND	EE: ↓ AUC by 35%, ↓ Cmax by 20% NE: ↓ AUC by 46%	Patients should be advised to use additional or alternative methods of contraception.
Theophylline	5 mg/kg	300 mg X 14 days	Healthy subjects (11)	ND	↔

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Figure 1: Effect of interacting drugs on the pharmacokinetics of venlafaxine and active metabolite O-desmethylvenlafaxine (ODV).

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Table 6: Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (C_max and AUC_τ after 200 mg q12h)	Recommendations for Voriconazole Dosage Adjustment/Comments
RifampinResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg q12h voriconazole to healthy subjects and Rifabutin (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (400 mg q24h) Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (300 mg q24h) (CYP450 Induction)	Slight Decrease in AUC _τ	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h) (CYP450 Induction) Low-dose Ritonavir (100 mg q12h) (CYP450 Induction)	Significantly Reduced Reduced	Contraindicated Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Phenytoin (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John's Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure) A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to voriconazole Careful assessment of voriconazole effectiveness

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Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2) ].
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.9) ].
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.11) and Use in Specific Populations (8.5) ].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs [see Adverse Reactions (6.1) ].
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions (5.16) ].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution Two-fold increase in exposure	Monitor for sildenafil toxicity [see Clinical Pharmacology (12.3) ].
Duloxetine	Avoid Use Five-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx^®(didanosine) chewable/ buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2.4) ].	Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( 7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( 7)
Phenytoin	Monitor phenytoin level ( 7)
Methotrexate	Monitor for methotrexate toxicity ( 7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine ( 7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin ( 7)

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.10, 7.3)

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of this product. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.12, 7.3)

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Summary of antiepileptic drug (AED) interactions with topiramate (7.1).
AED co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazaepine (CBZ)	NC	40% decrease
CBZ epoxideIs not administered but is an active metabolite of carbamazepine	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400mg/day	13% decrease

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Table 4: Clinically Relevant Interactions Affecting Omeprazole When Co-Administered with Other Drugs
CYP2C19 or CYP3A4 Inducers
Clinical Impact:	Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention:	St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions (5.9)]. Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:	Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
Intervention:	Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole.

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin	Monitor phenytoin level (7)
Methotrexate	Monitor for methotrexate toxicity (7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)

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Table 18. Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio Change relative to reference )		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	C_max	Risperidone Dose Recommendation
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 mg or 3 mg twice daily	1.4	1.5	Reevaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	--	Reevaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	--
	40 mg/day -	4 mg/day	1.8	--
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Drugs that Affect Renal Function	A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics	Dofetilide	Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
	Sotalol	Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
	Dronedarone	Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog	Teriparatide	Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement	Thyroid	Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics	Epinephrine Norepinephrine Dopamine	Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents	Succinylcholine	May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements	Calcium	If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers		Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.

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Table 13. Established and Other Potentially Significant Drug Interactions
↓= Decreased (induces lamotrigine glucuronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ?= Conflicting data.
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine ? CBZ epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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Antiarrhythmics	Dofetilide	Concomitant administration with digoxin was associated with a higher rate of torsades de pointes.
	Moricizine	Reported to increase PR interval and QRS duration. There are reports of first degree atrioventricular block or bundle branch block developing with digitalis administration. The known effects of moricizine on calcium conductance may explain the effects on atrioventricular node conduction.
	Sotalol	Proarrhythmic events even more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving dioxin.
Parathyroid Hormone Analog	Teriparatide	Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid Supplement	Thyroid	Treatment of hyperthyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics	Epinepherine	Can increase the risk of cardiac arrhythmias.
	Norepinephrine
	Dopamine
Neuromuscular Blocking Agents	Succinylcholine	May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements	Calcium	If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers	Additive effects on AV node conduction can result in complete heart block.

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Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C_max and AUCτ)	Recommendations for Drug Dosage Adjustment/Comments
Sirolimus* (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin* (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (400 mg q 24h) (CYP3A4 Inhibition) Efavirenz (300 mg q 24h) (CYP3A4 Inhibition)	Significantly Increased Slight decrease in AUC_t	Contraindicated When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)(CYP3A4 Inhibition) Low-dose Ritonavir (100 mg q12h)	No Significant Effect of Voriconazole on Ritonavir C_max or AUCτ Slight Decrease in Ritonavir C_max and AUCτ	Contraindicated because of significant reduction of voriconazole C_max and AUCτ
		Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole C_max and AUCτ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated
Cyclosporine* (CYP3A4 Inhibition)	AUCτ Significantly Increased; No Significant Effect on C_max	When initiating therapy with voriconazole in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
Methadone*** (CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see DRUG INTERACTIONS (7)]
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see DRUG INTERACTIONS (7)].
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see DRUG INTERACTIONS (7)].
NSAIDs**** including ibuprofen and diclofenac (CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed. [see DRUG INTERACTIONS (7)].
Tacrolimus* (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with voriconazole in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin* (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)**	Increased	Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin* (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	Monitor PT or other suitable anticoagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole* (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with voriconazole in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects on Indinavir Exposure	No dosage adjustment for indinavir when coadministered with voriconazole tablets
	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIs***** (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.
Everolimus (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Concomitant administration of voriconazole and everolimus is not recommended

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Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine (CBZ) and CBZ epoxide	? CBZ epoxide	May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Factors	Dosage Adjustments for Aripiprazole Tablets
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors	Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double usual dose over 1 to 2 weeks

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NA = Not available/reported
Digoxin concentrations increased greater than 50%
	Digoxin Serum Concentration Increase	Digoxin AUC Increase	Recommendations
Amiodarone	70%	NA	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
Captopril	58%	39%
Clarithromycin	NA	70%
Dronedarone	NA	150%
Gentamicin	129-212%	NA
Erythromycin	100%	NA
Itraconazole	80%	NA
Lapatinib	NA	180%
Propafenone	NA	60-270%
Quinidine	100%	NA
Ranolazine	50%	NA
Ritonavir	NA	86%
Telaprevir	50%	85%
Tetracycline	100%	NA
Verapamil	50-75%	NA
Digoxin concentrations increased less than 50%
Atorvastatin	22%	15%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
Carvedilol	16%	14%
Conivaptan	33%	43%
Diltiazem	20%	NA
Indomethacin	40%	NA
Nefazodone	27%	15%
Nifedipine	45%	NA
Propantheline	24%	24%
Quinine	NA	33%
Rabeprazole	29%	19%
Saquinavir	27%	49%
Spironolactone	25%	NA
Telmisartan	20-49%	NA
Ticagrelor	31%	28%
Tolvaptan	30%	20%
Trimethoprim	22-28%	NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate and sulfasalazine			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20-40% as necessary.

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Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin Tablets, USP
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)]
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate. [See Warnings and Precautions (5.6).]
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [See Adverse Reactions (6.1).]
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with Ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution Two-fold increase in exposure	Monitor for sildenafil toxicity (see Pharmacokinetics 12.3).
Duloxetine	Avoid Use Five-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin Tablets, USP
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration. (2)].	Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

Table name:

Classes of Drug
also: other medications affecting blood elements which may modify hemostasis dietary deficiencies prolonged hot weather unreliable PT/INR determinations
5-lipoxygenase Inhibitor	Antiplatelet Drugs/Effects	Leukotriene Receptor Antagonist
Adrenergic Stimulants, Central	Antithyroid Drugs^†	Monoamine Oxidase Inhibitors
Alcohol Abuse Reduction	Beta-Adrenergic Blockers	Narcotics, prolonged
Preparations	Cholelitholytic Agents	Nonsteroidal Anti-
Analgesics	Diabetes Agents, Oral	Inflammatory Agents
Anesthetics, Inhalation	Diuretics^†	Proton Pump Inhibitors
Antiandrogen	Fungal Medications,	Psychostimulants
Antiarrhythmics^†	Intravaginal, Systemic^†	Pyrazolones
Antibiotics^†	Gastric Acidity and Peptic	Salicylates
Aminoglycosides (oral)	Ulcer Agents^†	Selective Serotonin
Cephalosporins, parenteral	Gastrointestinal	Reuptake Inhibitors
Macrolides	Prokinetic Agents	Steroids, Adrenocortical^†
Miscellaneous	Ulcerative Colitis Agents	Steroids, Anabolic (17-Alkyl
Penicillins, intravenous,	Gout Treatment Agents	Testosterone Derivatives)
high dose	Hemorrheologic Agents	Thrombolytics
Quinolones (fluoroquinolones)	Hepatotoxic Drugs	Thyroid Drugs
Sulfonamides, long acting	Hyperglycemic Agents	Tuberculosis Agents^†
Tetracyclines	Hypertensive Emergency Agents	Uricosuric Agents
Anticoagulants	Hypnotics^†	Vaccines
Anticonvulsants^†	Hypolipidemics^†	Vitamins^†
Antidepressants^†	Bile Acid-Binding Resins^†
Antimalarial Agents	Fibric Acid Derivatives
Antineoplastics^†	HMG-CoA Reductase Inhibitors^†
Antiparasitic/Antimicrobials
Specific Drugs Reported
acetaminophen	fenoprofen	paroxetine
alcoholIncreased and decreased PT/INR responses have been reported.	fluconazole	penicillin G, intravenous
allopurinol	fluorouracil	pentoxifylline
aminosalicylic acid	fluoxetine	phenylbutazone
amiodarone HCl	flutamide	phenytoin
argatroban	fluvastatin	piperacillin
aspirin	fluvoxamine	piroxicam
atenolol	gefitinib	pravastatin
atorvastatin	gemfibrozil	prednisone
azithromycin	glucagon	propafenone
bivalirudin	halothane	propoxyphene
capecitabine	heparin	propranolol
cefamandole	ibuprofen	propylthiouracil
cefazolin	ifosfamide	quinidine
cefoperazone	indomethacin	quinine
cefotetan	influenza virus vaccine	rabeprazole
cefoxitin	itraconazole	ranitidine
ceftriaxone	ketoprofen	rofecoxib
celecoxib	ketorolac	sertraline
cerivastatin	lansoprazole	simvastatin
chenodiol	lepirudin	stanozolol
chloramphenicol	levamisole	streptokinase
chloral hydrate	levofloxacin	sulfamethizole
chlorpropamide	levothyroxine	sulfamethoxazole
cholestyramine	liothyronine	sulfinpyrazone
cimetidine	lovastatin	sulfisoxazole
ciprofloxacin	mefenamic acid	sulindac
cisapride	methimazole	tamoxifen
clarithromycin	methyldopa	tetracycline
clofibrate	methylphenidate	thyroid
warfarin sodium overdose	methylsalicylate ointment (topical)	ticarcillin
cyclophosphamide	metronidazole	ticlopidine
danazol	miconazole	tissue plasminogen
dextran	(intravaginal, oral, systemic)	activator (t-PA)
dextrothyroxine	moricizine hydrochloride	tolbutamide
diazoxide	nalidixic acid	tramadol
diclofenac	naproxen	trimethoprim/sulfamethoxazole
dicumarol	neomycin	urokinase
diflunisal	norfloxacin	valdecoxib
disulfiram	ofloxacin	valproate
doxycycline	olsalazine	vitamin E
erythromycin	omeprazole	zafirlukast
esomeprazole	oxandrolone	zileuton
ethacrynic acid	oxaprozin
ezetimibe	oxymetholone
fenofibrate	pantoprazole

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Interacting Drug	Interaction
Multivalent cation - containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.12, 7.3)

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Bleeding times
Clinical Impact:	Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention:	This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact:	The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention:	Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with NAPRELAN be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact:	Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention:	This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid are determined.

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Table 4. Sevelamer Drug Interactions
Oral drugs for which sevelamer did not alter the pharmacokinetics when administered concomitantly
Digoxin Enalapril Iron Metoprolol Warfarin
Oral drugs that have demonstrated interaction with sevelamer and are to be dosed separately from Renvela
Ciprofloxacin Mycophenolate mofetil	Dosing Recommendations Take at least 2 hours before or 6 hours after sevelamer Take at least 2 hours before sevelamer

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Table 4: Drugs Having Clinically Important Interactions with Amphetamines
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact	Concomitant use of MAOIs and CNS stimulants can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure.
Intervention	Do not administer MAS-ER Capsules concomitantly or within 14 days after discontinuing MAOI [see CONTRAINDICATIONS (4) and WARNINGS AND PRECAUTIONS (5.6)].
Examples	selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
Serotonergic Drugs
Clinical Impact	The concomitant use of MAS-ER Capsules and serotonergic drugs increases the risk of serotonin syndrome.
Intervention	Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome, particularly during MAS-ER Capsules initiation or dosage increase. If serotonin syndrome occurs, discontinue MAS-ER Capsules and the concomitant serotonergic drug(s) [see WARNINGS AND PRECAUTIONS (5.6)].
Examples	selective serotonin reuptake inhibitors (SSRI), serotonin norepinephrine reuptake inhibitors (SNRI), triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John's Wort
CYP2D6 Inhibitors
Clinical Impact	The concomitant use of MAS-ER Capsules and CYP2D6 inhibitors may increase the exposure of MAS-ER Capsules compared to the use of the drug alone and increase the risk of serotonin syndrome.
Intervention	Initiate with lower doses and monitor patients for signs and symptoms of serotonin syndrome particularly during MAS-ER Capsules initiation and after a dosage increase. If serotonin syndrome occurs, discontinue MAS-ER Capsules and the CYP2D6 inhibitor [see WARNINGS AND PRECAUTIONS (5.6) and OVERDOSAGE (10)].
Examples	paroxetine and fluoxetine (also serotonergic drugs), quinidine, ritonavir
Alkalinizing Agents
Clinical Impact	Increase blood levels and potentiate the action of amphetamine.
Intervention	Co-administration of MAS-ER Capsules and gastrointestinal or urinary alkalinizing agents should be avoided.
Examples	Gastrointestinal alkalinizing agents (e.g., sodium bicarbonate). Urinary alkalinizing agents (e.g. acetazolamide, some thiazides).
Acidifying Agents
Clinical Impact	Lower blood levels and efficacy of amphetamines.
Intervention	Increase dose based on clinical response.
Examples	Gastrointestinal acidifying agents (e.g., guanethidine, reserpine, glutamic acid HCl, ascorbic acid). Urinary acidifying agents (e.g., ammonium chloride, sodium acid phosphate, methenamine salts).
Tricyclic Antidepressants
Clinical Impact	May enhance the activity of tricyclic or sympathomimetic agents causing striking and sustained increases in the concentration of d-amphetamine in the brain; cardiovascular effects can be potentiated.
Intervention	Monitor frequently and adjust or use alternative therapy based on clinical response.
Examples	desipramine, protriptyline
Proton Pump Inhibitors
Clinical Impact	Time to maximum concentration (Tmax) of amphetamine is decreased compared to when administered alone.
Intervention	Monitor patients for changes in clinical effect and adjust therapy based on clinical response.
Examples	omeprazole

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Table 3. Comparison of Clopidogrel Active Metabolite Exposure and Platelet Inhibition with and without Proton Pump Inhibitors, Omeprazole and Pantoprazole

	% Change from Plavix (300 mg/75 mg) alone
Plavix plus	Cmax (ng/mL)		AUC		Platelet InhibitionInhibition of platelet aggregation with 5 mcM ADP (%)
	Day 1	Day 5	Day 1	Day 5AUC at Day 5 is AUC_0-24	Day 1	Day 5
OmeprazoleSimilar results seen when Plavix and omeprazole were administered 12 hours apart. 80 mg	↓46%	↓42%	↓45%	↓40%	↓39%	↓21%
Pantoprazole 80 mg	↓24%	↓28%	↓20%	↓14%	↓15%	↓11%

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Table 5. Drugs That May Decrease Conversion of T4 to T3
Potential impact: Administration of these enzyme inhibitors decreases the peripheral conversion of T4 to T3, leading to decreased T3 levels. However, serum T4 levels are usually normal but may occasionally be slightly increased.
Drug or Drug Class	Effect
Beta-adrenergic antagonists (e.g., Propranolol > 160 mg/day)	In patients treated with large doses of propranolol (> 160 mg/day), T3 and T4 levels change, TSH levels remain normal, and patients are clinically euthyroid. Actions of particular beta-adrenergic antagonists may be impaired when a hypothyroid patient is converted to the euthyroid state.
Glucocorticoids (e.g., Dexamethasone > 4 mg/day)	Short-term administration of large doses of glucocorticoids may decrease serum T3 concentrations by 30% with minimal change in serum T4 levels. However, long-term glucocorticoid therapy may result in slightly decreased T3 and T4 levels due to decreased TBG production (See above).
Other drugs: Amiodarone	Amiodarone inhibits peripheral conversion of levothyroxine (T4) to triiodothyronine (T3) and may cause isolated biochemical changes (increase in serum free-T4, and decreased or normal free-T3) in clinically euthyroid patients.

Table name:

Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine, danazol	Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

Table name:

Drug	Description
Corticosteroids	Decreases plasma salicylate level; Tapering doses of steroids may promote salicylism
Ammonium Sulfate	Increases plasma salicylate level

Table name:

Table 9. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug Name	Effect on Concentration of Lopinavir or Concomitant Drug	Clinical Comment
HIV-1 Antiviral Agents
Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz, nevirapine	↓ lopinavir	KALETRA dose increase is recommended in all patients [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)]. Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz. Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz. KALETRA should not be administered once daily in combination with efavirenz or nevirapine [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine	↑ lopinavir	Appropriate doses of the combination with respect to safety and efficacy have not been established.
Nucleoside Reverse Transcriptase Inhibitor: didanosine		KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).
Nucleoside Reverse Transcriptase Inhibitor: tenofovir	↑ tenofovir	KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitor: abacavir zidovudine	↓ abacavir ↓ zidovudine	KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.
HIV-1 Protease Inhibitor: amprenavir*	↑ amprenavir ↓ lopinavir	KALETRA should not be administered once daily in combination with amprenavir [see Dosage and Administration (2.1)].
HIV-1 Protease Inhibitor: fosamprenavir/ritonavir	↓ amprenavir ↓ lopinavir	An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: indinavir*	↑ indinavir	Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily [see Clinical Pharmacology (12.3)]. KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor: nelfinavir*	↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir	KALETRA should not be administered once daily in combination with nelfinavir [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
HIV-1 Protease Inhibitor: ritonavir*	↑ lopinavir	Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: saquinavir*	↑ saquinavir	The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor: tipranavir	↓ lopinavir AUC and C_min	KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily).
HIV CCR5 – antagonist: maraviroc	↑ maraviroc	Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry^® (maraviroc).
Other Agents
Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), and quinidine	↑ antiarrhythmics	Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.
Anticancer Agents: vincristine, vinblastine, dasatinib, nilotinib	↑ anticancer agents	Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents. For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.
Anticoagulant: warfarin		Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: carbamazepine, phenobarbital, phenytoin	↓ lopinavir ↓ phenytoin	KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
Antidepressant: bupropion	↓ bupropion ↓ active metabolite, hydroxybupropion	Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant: trazodone	↑ trazodone	Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-infective: clarithromycin	↑ clarithromycin	For patients with renal impairment, the following dosage adjustments should be considered: • For patients with CL_CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. • For patients with CL_CR < 30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary.
Antifungals: ketoconazole*, itraconazole, voriconazole	↑ ketoconazole ↑ itraconazole ↓ voriconazole	High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended. Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients.
Anti-gout: colchicine	↑ colchicine	Patients with renal or hepatic impairment should not be given colchicine with KALETRA. Treatment of gout flares-co-administration of colchicine in patients on KALETRA: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on KALETRA: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial: rifabutin*	↑ rifabutin and rifabutin metabolite	Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antimycobacterial: rifampin	↓ lopinavir	May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone [see Clinical Pharmacology (12.3) for magnitude of interaction].
Antiparasitic: atovaquone	↓ atovaquone	Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Benzodiazepines: parenterally administered midazolam	↑ midazolam	Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam [see Contraindications (4)]. If KALETRA is coadministered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Calcium Channel Blockers, dihydropyridine: e.g., felodipine, nifedipine, nicardipine	↑ dihydropyridine calcium channel blockers	Caution is warranted and clinical monitoring of patients is recommended.
Contraceptive: ethinyl estradiol*	↓ ethinyl estradiol	Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.
Corticosteroid: dexamethasone	↓ lopinavir	Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly.
disulfiram/metronidazole		KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Endothelin receptor antagonists: bosentan	↑ bosentan	Co-administration of bosentan in patients on KALETRA: In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Co-administration of KALETRA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA. After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin	↑ atorvastatin ↑ rosuvastatin	Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with KALETRA.
Immunosuppressants: cyclosporine, tacrolimus, rapamycin	↑ immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Inhaled Steroid: fluticasone	↑ fluticasone	Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect.
Long-acting beta-adrenoceptor agonist: salmeterol	↑ salmeterol	Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic: methadone* fentanyl	↓ methadone ↑ fentanyl	Dosage of methadone may need to be increased when co-administered with KALETRA. Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA.
PDE5 inhibitors: sildenafil, tadalafil, vardenafil	↑ sildenafil ↑ tadalafil ↑ vardenafil	Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio^®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA [see Contraindications (4)]. The following dose adjustments are recommended for use of tadalafil (Adcirca^®) with KALETRA: Co-administration of ADCIRCA in patients on KALETRA: In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Co-administration of KALETRA in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: It is recommended not to exceed the following doses: • Sildenafil: 25 mg every 48 hours • Tadalafil: 10 mg every 72 hours • Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events.
* see Clinical Pharmacology (12.3) for Magnitude of Interaction.

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Table 25: Clinically Important Drug Interactions with ABILIFY:
Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of ABILIFY with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of ABILIFY alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of ABILIFY with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the ABILIFY dosage [see DOSAGE AND ADMINISTRATION (2.7)] .
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of ABILIFY and carbamazepine decreased the exposure of aripiprazole compared to the use of ABILIFY alone [see CLINICAL PHARMACOLOGY (12.3)] .	With concomitant use of ABILIFY with a strong CYP3A4 inducer, consider increasing the ABILIFY dosage [see DOSAGE AND ADMINISTRATION (2.7)] .
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.8) ].
Benzodiazepines (e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.8) ]	Monitor sedation and blood pressure. Adjust dose accordingly.

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Table 23: Clinically Important Drug Interactions with Aripiprazole:
Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [ see CLINICAL PHARMACOLOGY ( 12 . 3 )].	With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [ see DOSAGE AND ADMINISTRATION ( 2 . 7 )].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [ see CLINICAL PHARMACOLOGY ( 12 . 3 )].	With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [ see DOSAGE AND ADMINISTRATION ( 2 . 7 )].
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [ see WARNINGS AND PRECAUTIONS ( 5 . 7 )].
Benzodiazepines (e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepamalone [ see WARNINGS AND PRECAUTIONS ( 5 . 7 )]	Monitor sedation and blood pressure. Adjust dose accordingly.

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Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [ see Contraindications (4.2) ] .
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [ s ee Warnings and Precautions (5.9) ] .
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.11) and Use in Specific Populations (8.5) ].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were coadministered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is coadministered with oral antidiabetic drugs [ s ee Adverse Reactions (6.1) ] .
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is coadministered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after coadministration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.16) ].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after coadministration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution Two-fold increase in exposure	Monitor for sildenafil toxicity [ s ee C li n ic a l Pha r m a c o l og y ( 1 2 .3)].
Duloxetine	Avoid Use Five-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx^® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2.4) ].	Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

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* Antacids may affect absorption of phenytoin. † The induction potency of St. John's wort may vary widely based on preparation.
Interacting Agent	Examples
Drugs that may increase phenytoin serum levels
Antiepileptic drugs	Ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate
Azoles	Fluconazole, ketoconazole, itraconazole, miconazole, voriconazole
Antineoplastic agents	Capecitabine, fluorouracil
Antidepressants	Fluoxetine, fluvoxamine, sertraline
Gastric acid reducing agents	H₂ antagonists (cimetidine), omeprazole
Sulfonamides	Sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim
Other	Acute alcohol intake, amiodarone, chloramphenicol, chlordiazepoxide, disulfiram, estrogen, fluvastatin, isoniazid, methylphenidate, phenothiazines, salicylates, ticlopidine, tolbutamide, trazodone, warfarin
Drugs that may decrease phenytoin serum levels
Antacids*	Calcium carbonate, aluminum hydroxide, magnesium hydroxide Prevention or Management: Phenytoin and antacids should not be taken at the same time of day
Antineoplastic agents usually in combination	Bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate
Antiviral agents	Fosamprenavir, nelfinavir, ritonavir
Antiepileptic drugs	Carbamazepine, vigabatrin
Other	Chronic alcohol abuse, diazepam, diazoxide, folic acid, reserpine, rifampin, St. John's wort^†, sucralfate, theophylline
Drugs that may either increase or decrease phenytoin serum levels
Antiepileptic drugs	Phenobarbital, valproate sodium, valproic acid

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CONCOMITANT DRUG	CLINICAL EFFECT(S)
Amphetamines, cocaine, other sympathomimetic agents	Additive hypertension, tachycardia, possibly cardiotoxicity
Atropine, scopolamine, antihistamines, other anticholinergic agents	Additive or super-additive tachycardia, drowsiness
Amitriptyline, amoxapine, desipramine, other tricyclic antidepressants	Additive tachycardia, hypertension, drowsiness
Barbiturates, benzodiazepines, ethanol, lithium, opioids, buspirone, antihistamines, muscle relaxants, other CNS depressants	Additive drowsiness and CNS depression
Disulfiram	A reversible hypomanic reaction was reported in a 28 y/o man who smoked marijuana; confirmed by dechallenge and rechallenge
Fluoxetine	A 21 y/o female with depression and bulimia receiving 20 mg/day fluoxetine X 4 wks became hypomanic after smoking marijuana; symptoms resolved after 4 days
Antipyrine, barbiturates	Decreased clearance of these agents, presumably via competitive inhibition of metabolism
Theophylline	Increased theophylline metabolism reported with smoking of marijuana; effect similar to that following smoking tobacco

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Specific Drugs Reported
also: other medications affecting blood elements which may modify hemostasis dietary deficiencies prolonged hot weather unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported.
acetaminophen alcohol† allopurinol aminosalicylic acid amiodarone HCl argatroban aspirin atenolol atorvastatin† azithromycin bivalirudin capecitabine cefamandole cefazolin cefoperazone cefotetan cefoxitin ceftriaxone celecoxib cerivastatin chenodiol chloramphenicol chloral hydrate† chlorpropamide cholestyramine† cimetidine ciprofloxacin cisapride clarithromycin clofibrate cyclophosphamide† danazol dextran dextrothyroxine diazoxide	diclofenac dicumarol diflunisal disulfiram doxycycline erythromycin esomeprazole ethacrynic acid ezetimibe fenofibrate fenoprofen fluconazole fluorouracil fluoxetine flutamide fluvastatin fluvoxamine gefitinib gemifibrozil glucagon halothane heparin ibuprofen ifosfamide indomethacin influenza virus vaccine itraconazole ketoprofen ketorolac lansoprazole lepirudin levamisole levofloxacin levothyroxine liothyronine	lovastatin mefenamic acid methimazole† methyldopa methylphenidate methylsalicylate ointment (topical) metronidazole miconazole (intravaginal, oral, systemic) moricizine hydrochloride† nalidixic acid naproxen neomycin norfloxacin ofloxacin olsalazine omeprazole oxandrolone oxaprozin oxymetholone pantoprazole paroxetine penicillin G, intravenous pentoxifylline phenylbutazone phenytoin† piperacillin piroxicam pravastatin† prednisone† propafenone	propoxyphene propranolol propylthiouracil† quinidine quinine rabeprazole ranitidine† rofecoxib sertraline simvastatin stanozolol streptokinase sulfamethizole sulfamethoxazole sulfinpyrazone sulfisoxazole sulindac tamoxifen tetracycline thyroid ticarcillin ticlopidine tissue plasminogen activator (t-PA) tolbutamide tramadol trimethoprim/ sulfamethoxazole urokinase valdecoxib valproate vitamin E warfarin overdose zafirlukast zileuton

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Figure 6: Mean Standing Systolic Blood Pressure Change from Baseline

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine concentrations approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine and carbamazepine epoxide	? carbamazepine epoxide	May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
*Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	C _max
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing.
	20 mg/day	4 mg/day	1.6	-	Do not exceed 8 mg/day
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers)
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio*)		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	Cmax
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Table 2: Clinically Significant Drug Interactions with diclofenac
Drugs That Interfere with Hemostasis
Clinical Impact:	Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case- control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of CAMBIA with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)]
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].
Intervention:	Concomitant use of CAMBIA and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)].
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta- blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of CAMBIA and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of CAMBIA and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)].
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of CAMBIA with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)].
Clinical Impact:	The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of CAMBIA and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of CAMBIA and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of CAMBIA and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of CAMBIA and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of CAMBIA and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention:	The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of CAMBIA and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of NSAIDs and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Inhibitors of Cytochrome P450 2C9
Clinical Impact:	Diclofenac is metabolized predominantly by Cytochrome P-450 CYP2C9. Co- administration of medications that inhibit CYP2C9 may affect the pharmacokinetics of diclofenac [see Warnings and Precautions (12.3)]
Intervention:	During concomitant use of CAMBIA and drugs that inhibit CYP2C9, an increase in the duration between CAMBIA doses for subsequent migraine attacks may be necessary.

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Table 3: Mean (95% C.I.) maximal change from baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in BPH patients on stable alpha-blocker therapy with tamsulosin 0.4 or 0.8 mg daily (Study 2)
	Vardenafil 10 mg Placebo-subtracted	Vardenafil 20 mg Placebo-subtracted
Standing SBP	-4 (-6.8, -0.3)	-4 (-6.8, -1.4)
Supine SBP	-5 (-8.2, -0.8)	-4 (-6.3, -1.8)

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Bleeding times
Clinical Impact:	Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention:	This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact:	The administration of naproxen may result in increased urinary values for 17 ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention:	Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact:	Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention:	This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.

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Bleeding times
Clinical Impact:	Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention:	This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact:	The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention:	Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact:	Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention:	This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitors (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
Drug Name	Effect on Concentration of Nevirapine or Concomitant Drug	Clinical Comment
Atazanavir/Ritonavir	↓ Atazanavir ↑ Nevirapine	Do not coadminister nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure.
Clarithromycin	↓ Clarithromycin ↑ 14-OH clarithromycin	Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Efavirenz	↓ Efavirenz	There has been no determination of appropriate doses for the safe and effective use of this combination [see Warnings and Precautions (5.4) ].
Ethinyl estradiol and Norethindrone	↓ Ethinyl estradiol ↓ Norethindrone	Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.
Fluconazole	↑ Nevirapine	Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration and patients should be monitored closely for nevirapine-associated adverse events.
Fosamprenavir	↓ Amprenavir ↑ Nevirapine	Coadministration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir	↓ Amprenavir ↑ Nevirapine	No dosing adjustments are required when nevirapine is coadministered with 700 mg/100 mg of fosamprenavir/ritonavir twice daily.
Indinavir	↓ Indinavir	Appropriate doses for this combination are not established, but an increase in the dosage of indinavir may be required.
Ketoconazole	↓ Ketoconazole	Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Lopinavir/Ritonavir	↓ Lopinavir	A dose increase of lopinavir/ritonavir tablets to 500 mg/125 mg twice daily is recommended when used in combination with nevirapine. A dose increase of lopinavir/ritonavir oral solution to 533 mg/133 mg twice daily with food is recommended in combination with nevirapine. In children 6 months to 12 years of age receiving lopinavir/ritonavir solution, consideration should be given to increasing the dose of lopinavir/ritonavir to 13/3.25 mg/kg for those 7 kg to < 15 kg; 11/2.75 mg/kg for those 15 kg to 45 kg; up to a maximum dose of 533 mg/133 mg twice daily. Refer to the lopinavir/ritonavir package insert for complete pediatric dosing instructions when lopinavir/ritonavir tablets are used in combination with nevirapine.
Methadone	↓ Methadone	Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Nelfinavir	↓ Nelfinavir M8 Metabolite ↓ Nelfinavir C_min	The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established.
Rifabutin	↑ Rifabutin	Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin	↓ Nevirapine	Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Saquinavir/Ritonavir	The interaction between nevirapine and saquinavir/ritonavir has not been evaluated	The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
Potential Drug Interactions:
Drug Class	Examples of Drugs
Antiarrhythmics	Amiodarone, disopyramide, lidocaine	Plasma concentrations may be decreased.
Anticonvulsants	Carbamazepine, clonazepam, ethosuximide	Plasma concentrations may be decreased.
Antifungals	Itraconazole	Plasma concentrations of some azole antifungals may be decreased. Nevirapine and itraconazole should not be administered concomitantly due to a potential decrease in itraconazole plasma concentrations.
Calcium channel blockers	Diltiazem, nifedipine, verapamil	Plasma concentrations may be decreased.
Cancer chemotherapy	Cyclophosphamide	Plasma concentrations may be decreased.
Ergot alkaloids	Ergotamine	Plasma concentrations may be decreased.
Immunosuppressants	Cyclosporin, tacrolimus, sirolimus	Plasma concentrations may be decreased.
Motility agents	Cisapride	Plasma concentrations may be decreased.
Opiate agonists	Fentanyl	Plasma concentrations may be decreased.
Antithrombotics	Warfarin	Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.

Table name:

Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( 7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( 7)
Phenytoin	Monitor phenytoin level ( 7)
Methotrexate	Monitor for methotrexate toxicity ( 7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine ( 7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin ( 7)

Table name:

Table 3Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

Table name:

Table 5. Established and Other Potentially Significant Drug Interactions
↓= Decreased (induces lamotrigine glucuronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
C oncomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓levonorgestrel	Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and Carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

Table name: 0.6 mg (1 tablet) for 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Not to be repeated before 3 days.Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.

If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.Treatment of familial Mediterranean fever (FMF): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).For patients who have been receiving REYATAZ/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based on individual tolerability.Coadministration of REYATAZ/ritonavir in patients on bosentan: Discontinue bosentan at least 36 hours before starting REYATAZ/ritonavir. At least 10 days after starting REYATAZ/ritonavir, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability.Use of REVATIO^® (sildenafil) for the treatment of pulmonary hypertension (PAH) is contraindicated with REYATAZ [see Contraindications (4) ].

The following dose adjustments are recommended for the use of ADCIRCA^® (tadalafil) with REYATAZ:

Coadministration of ADCIRCA^® in patients on REYATAZ (with or without ritonavir):
For patients receiving REYATAZ (with or without ritonavir) for at least one week, start ADCIRCA^® at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability.

Coadministration of REYATAZ (with or without ritonavir) in patients on ADCIRCA^®:
Avoid the use of ADCIRCA^® when starting REYATAZ (with or without ritonavir). Stop ADCIRCA^® at least 24 hours before starting REYATAZ (with or without ritonavir). At least one week after starting REYATAZ (with or without ritonavir), resume ADCIRCA^® at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability.

Table 13: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies^a or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated)
Concomitant Drug Class: Specific Drugs	Effect on Concentration of Atazanavir or Concomitant Drug	Clinical Comment
^a For magnitude of interactions see Clinical Pharmacology, Tables 17 and 18 (12.3) .
^b See Contraindications (4), Table 3 for orally administered midazolam.
^c In combination with atazanavir 300 mg and ritonavir 100 mg once daily.
^d In combination with atazanavir 400 mg once daily.
HIV Antiviral Agents
Nucleoside Reverse Transcriptase Inhibitors (NRTIs): didanosine buffered formulations enteric-coated (EC) capsules	↓ atazanavir ↓ didanosine	Coadministration of REYATAZ with didanosine buffered tablets resulted in a marked decrease in atazanavir exposure. It is recommended that REYATAZ be given (with food) 2 h before or 1 h after didanosine buffered formulations. Simultaneous administration of didanosine EC and REYATAZ with food results in a decrease in didanosine exposure. Thus, REYATAZ and didanosine EC should be administered at different times.
Nucleotide Reverse Transcriptase Inhibitors: tenofovir disoproxil fumarate	↓ atazanavir ↑ tenofovir	Tenofovir may decrease the AUC and C_min of atazanavir. When coadministered with tenofovir, it is recommended that REYATAZ 300 mg be given with ritonavir 100 mg and tenofovir 300 mg (all as a single daily dose with food). REYATAZ without ritonavir should not be coadministered with tenofovir. REYATAZ increases tenofovir concentrations. The mechanism of this interaction is unknown. Higher tenofovir concentrations could potentiate tenofovir-associated adverse events, including renal disorders. Patients receiving REYATAZ and tenofovir should be monitored for tenofovir-associated adverse events. For pregnant women taking REYATAZ with ritonavir and tenofovir, see Dosage and Administration (2.3) .
Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs): efavirenz	↓ atazanavir	Efavirenz decreases atazanavir exposure. In treatment-naive patients: If REYATAZ is combined with efavirenz, REYATAZ 400 mg (two 200-mg capsules) with ritonavir 100 mg should be administered once daily all as a single dose with food, and efavirenz 600 mg should be administered once daily on an empty stomach, preferably at bedtime. In treatment-experienced patients: Do not coadminister REYATAZ with efavirenz in treatment-experienced patients due to decreased atazanavir exposure.
Non-nucleoside Reverse Transcriptase Inhibitors: nevirapine	↓ atazanavir ↑ nevirapine	Do not coadminister REYATAZ with nevirapine because: Nevirapine substantially decreases atazanavir exposure. Potential risk for nevirapine associated toxicity due to increased nevirapine exposures.
Protease Inhibitors: saquinavir (soft gelatin capsules)	↑ saquinavir	Appropriate dosing recommendations for this combination, with or without ritonavir, with respect to efficacy and safety have not been established. In a clinical study, saquinavir 1200 mg coadministered with REYATAZ 400 mg and tenofovir 300 mg (all given once daily) plus nucleoside analogue reverse transcriptase inhibitors did not provide adequate efficacy [see Clinical Studies (14.2) ].
Protease Inhibitors: ritonavir	↑ atazanavir	If REYATAZ is coadministered with ritonavir, it is recommended that REYATAZ 300 mg once daily be given with ritonavir 100 mg once daily with food. See the complete prescribing information for NORVIR^® (ritonavir) for information on drug interactions with ritonavir.
Protease Inhibitors: others	↑ other protease inhibitor	REYATAZ/ritonavir: Although not studied, the coadministration of REYATAZ/ritonavir and other protease inhibitors would be expected to increase exposure to the other protease inhibitor. Such coadministration is not recommended.
Other Agents
Antacids and buffered medications	↓ atazanavir	Reduced plasma concentrations of atazanavir are expected if antacids, including buffered medications, are administered with REYATAZ. REYATAZ should be administered 2 hours before or 1 hour after these medications.
Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), quinidine	↑ amiodarone, bepridil, lidocaine (systemic), quinidine	Coadministration with REYATAZ has the potential to produce serious and/or life-threatening adverse events and has not been studied. Caution is warranted and therapeutic concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ (atazanavir sulfate).
Anticoagulants: warfarin	↑ warfarin	Coadministration with REYATAZ has the potential to produce serious and/or life-threatening bleeding and has not been studied. It is recommended that INR (International Normalized Ratio) be monitored.
Antidepressants: tricyclic antidepressants	↑ tricyclic antidepressants	Coadministration with REYATAZ has the potential to produce serious and/or life-threatening adverse events and has not been studied. Concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ.
trazodone	↑ trazodone	Concomitant use of trazodone and REYATAZ with or without ritonavir may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as REYATAZ, the combination should be used with caution and a lower dose of trazodone should be considered.
Antifungals: ketoconazole, itraconazole	REYATAZ/ritonavir: ↑ ketoconazole ↑ itraconazole	Coadministration of ketoconazole has only been studied with REYATAZ without ritonavir (negligible increase in atazanavir AUC and C_max). Due to the effect of ritonavir on ketoconazole, high doses of ketoconazole and itraconazole (>200 mg/day) should be used cautiously with REYATAZ/ritonavir.
Antifungals: voriconazole	Effect is unknown	Coadministration of voriconazole with REYATAZ, with or without ritonavir, has not been studied. Administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%. Voriconazole should not be administered to patients receiving REYATAZ/ritonavir, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Coadministration of voriconazole with REYATAZ (without ritonavir) may increase atazanavir concentrations; however, no data are available.
Antigout: colchicine	↑ colchicine	REYATAZ should not be coadministered with colchicine to patients with renal or hepatic impairment. Recommended dosage of colchicine when administered with REYATAZ: Treatment of gout flares:
Antimycobacterials: rifabutin	↑ rifabutin	A rifabutin dose reduction of up to 75% (eg, 150 mg every other day or 3 times per week) is recommended. Increased monitoring for rifabutin-associated adverse reactions including neutropenia is warranted.
Benzodiazepines: parenterally administered midazolam^b	↑ midazolam	Concomitant use of parenteral midazolam with REYATAZ may increase plasma concentrations of midazolam. Coadministration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Coadministration of oral midazolam with REYATAZ is CONTRAINDICATED.
Calcium channel blockers: diltiazem	↑ diltiazem and desacetyl-diltiazem	Caution is warranted. A dose reduction of diltiazem by 50% should be considered. ECG monitoring is recommended. Coadministration of REYATAZ/ritonavir with diltiazem has not been studied.
eg, felodipine, nifedipine, nicardipine, and verapamil	↑ calcium channel blocker	Caution is warranted. Dose titration of the calcium channel blocker should be considered. ECG monitoring is recommended.
Endothelin receptor antagonists: bosentan	↓ atazanavir ↑ bosentan	Plasma concentrations of atazanavir may be decreased when bosentan is administered with REYATAZ without ritonavir. Coadministration of bosentan and REYATAZ without ritonavir is not recommended. Coadministration of bosentan in patients on REYATAZ/ritonavir:
HMG-CoA reductase inhibitors: atorvastatin, rosuvastatin	↑ atorvastatin ↑ rosuvastatin	Use the lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with REYATAZ (with or without ritonavir). The risk of myopathy, including rhabdomyolysis, may be increased when HIV protease inhibitors, including REYATAZ, are used in combination with these drugs.
H₂-Receptor antagonists	↓ atazanavir	Plasma concentrations of atazanavir were substantially decreased when REYATAZ 400 mg once daily was administered simultaneously with famotidine 40 mg twice daily, which may result in loss of therapeutic effect and development of resistance.
		In treatment-naive patients: REYATAZ 300 mg with ritonavir 100 mg once daily with food should be administered simultaneously with, and/or at least 10 hours after, a dose of the H₂-receptor antagonist. An H₂-receptor antagonist dose comparable to famotidine 20 mg once daily up to a dose comparable to famotidine 40 mg twice daily can be used with REYATAZ 300 mg with ritonavir 100 mg in treatment-naive patients. OR For patients unable to tolerate ritonavir, REYATAZ 400 mg once daily with food should be administered at least 2 hours before and at least 10 hours after a dose of the H₂-receptor antagonist. No single dose of the H₂-receptor antagonist should exceed a dose comparable to famotidine 20 mg, and the total daily dose should not exceed a dose comparable to famotidine 40 mg. However, REYATAZ should not be used without ritonavir in pregnant women.
		In treatment-experienced patients: Whenever an H₂-receptor antagonist is given to a patient receiving REYATAZ with ritonavir, the H₂-receptor antagonist dose should not exceed a dose comparable to famotidine 20 mg twice daily, and the REYATAZ and ritonavir doses should be administered simultaneously with, and/or at least 10 hours after, the dose of the H₂-receptor antagonist. REYATAZ 300 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with an H₂-receptor antagonist. For pregnant women taking REYATAZ with ritonavir and an H₂-receptor antagonist, see Dosage and Administration (2.3) . REYATAZ 400 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with both tenofovir and an H₂-receptor antagonist. For pregnant women taking REYATAZ with ritonavir and both tenofovir and an H₂-receptor antagonist, see Dosage and Administration (2.3) .
Hormonal contraceptives: ethinyl estradiol and norgestimate or norethindrone	↓ ethinyl estradiol ↑ norgestimate^c ↑ ethinyl estradiol ↑ norethindrone^d	Use with caution if coadministration of REYATAZ or REYATAZ/ritonavir with oral contraceptives is considered. If an oral contraceptive is administered with REYATAZ plus ritonavir, it is recommended that the oral contraceptive contain at least 35 mcg of ethinyl estradiol. If REYATAZ is administered without ritonavir, the oral contraceptive should contain no more than 30 mcg of ethinyl estradiol. Potential safety risks include substantial increases in progesterone exposure. The long-term effects of increases in concentration of the progestational agent are unknown and could increase the risk of insulin resistance, dyslipidemia, and acne. Coadministration of REYATAZ or REYATAZ/ritonavir with other hormonal contraceptives (eg, contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestogens other than norethindrone or norgestimate, or less than 25 mcg of ethinyl estradiol, has not been studied; therefore, alternative methods of contraception are recommended.
Immunosuppressants: cyclosporin, sirolimus, tacrolimus	↑ immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with REYATAZ (atazanavir sulfate).
Inhaled beta agonist: salmeterol	↑ salmeterol	Coadministration of salmeterol with REYATAZ is not recommended. Concomitant use of salmeterol and REYATAZ may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Inhaled/nasal steroid: fluticasone	REYATAZ ↑ fluticasone	Concomitant use of fluticasone propionate and REYATAZ (without ritonavir) may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use.
	REYATAZ/ritonavir ↑ fluticasone	Concomitant use of fluticasone propionate and REYATAZ/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression, have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Coadministration of fluticasone propionate and REYATAZ/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects [see Warnings and Precautions (5.1) ].
Macrolide antibiotics: clarithromycin	↑ clarithromycin ↓ 14-OH clarithromycin ↑ atazanavir	Increased concentrations of clarithromycin may cause QTc prolongations; therefore, a dose reduction of clarithromycin by 50% should be considered when it is coadministered with REYATAZ. In addition, concentrations of the active metabolite 14-OH clarithromycin are significantly reduced; consider alternative therapy for indications other than infections due to Mycobacterium avium complex. Coadministration of REYATAZ/ritonavir with clarithromycin has not been studied.
Opioids: Buprenorphine	↑ buprenorphine ↑ norbuprenorphine	Coadministration of buprenorphine and REYATAZ with or without ritonavir increases the plasma concentration of buprenorphine and norbuprenorphine. Coadministration of REYATAZ plus ritonavir with buprenorphine warrants clinical monitoring for sedation and cognitive effects. A dose reduction of buprenorphine may be considered. Coadministration of buprenorphine and REYATAZ with ritonavir is not expected to decrease atazanavir plasma concentrations. Coadministration of buprenorphine and REYATAZ without ritonavir may decrease atazanavir plasma concentrations. REYATAZ without ritonavir should not be coadministered with buprenorphine.
PDE5 inhibitors: sildenafil, tadalafil, vardenafil	↑ sildenafil ↑ tadalafil ↑ vardenafil	Coadministration with REYATAZ has not been studied but may result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):
		Use of PDE5 inhibitors for erectile dysfunction: Use VIAGRA^® (sildenafil) with caution at reduced doses of 25 mg every 48 hours with increased monitoring for adverse events. Use CIALIS^® (tadalafil) with caution at reduced doses of 10 mg every 72 hours with increased monitoring for adverse events. REYATAZ/ritonavir: Use LEVITRA^® (vardenafil) with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse events. REYATAZ: Use LEVITRA^® (vardenafil) with caution at reduced doses of no more than 2.5 mg every 24 hours with increased monitoring for adverse events.
Proton-pump inhibitors: omeprazole	↓ atazanavir	Plasma concentrations of atazanavir were substantially decreased when REYATAZ 400 mg or REYATAZ 300 mg/ritonavir 100 mg once daily was administered with omeprazole 40 mg once daily, which may result in loss of therapeutic effect and development of resistance.
		In treatment-naive patients: The proton-pump inhibitor dose should not exceed a dose comparable to omeprazole 20 mg and must be taken approximately 12 hours prior to the REYATAZ 300 mg with ritonavir 100 mg dose.
		In treatment-experienced patients: Proton-pump inhibitors should not be used in treatment-experienced patients receiving REYATAZ.

Table name:

Table 8: Drugs That are Affected by and Affecting ciprofloxacin
Drugs That are Affected by ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)]
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.9)].
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.11) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs [see Adverse Reactions (6.1)].
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution Two-fold increase in exposure	Monitor for sildenafil toxicity [see Clinical Pharmacology (12.3)].
Duloxetine	Avoid Use Five-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of ciprofloxacin
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

Table name:

Table 6: Selected Drug Interactions
Concomitant Drug Class: Drug Name	Effect on Concentration of Raltegravir	Clinical Comment
HIV-1-Antiviral Agents
atazanavir	↑	Atazanavir, a strong inhibitor of UGT1A1, increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
atazanavir/ritonavir	↑	Atazanavir/ritonavir increases plasma concentrations of raltegravir. However, since concomitant use of ISENTRESS with atazanavir/ritonavir did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
efavirenz	↓	Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
etravirine	↓	Etravirine reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
tipranavir/ritonavir	↓	Tipranavir/ritonavir reduces plasma concentrations of raltegravir. However, since comparable efficacy was observed for this combination relative to other ISENTRESS-containing regimens in Phase 3 studies 018 and 019, no dose adjustment is recommended.
Other Agents
omeprazole	↑	Coadministration of medicinal products that increase gastric pH (e.g., omeprazole) may increase raltegravir levels based on increased raltegravir solubility at higher pH. However, since concomitant use of ISENTRESS with proton pump inhibitors and H2 blockers did not result in a unique safety signal in Phase 3 studies, no dose adjustment is recommended.
rifampin	↓	Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of raltegravir. The recommended dosage of ISENTRESS is 800 mg twice daily during coadministration with rifampin.

Table name:

Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 Inhibitors, (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with ezetimibe and simvastatin tablets
Verapamil, diltiazem, dronedarone	Do not exceed ezetimibe and simvastatin tablets, 10 mg/10 mg daily
Amiodarone, amlodipine, ranolazine	Do not exceed ezetimibe and simvastatin tablets, 10 mg/20 mg daily
Lomitapide	For patients with HoFH, do not exceed 10 mg/20 mg ezetimibe and simvastatin tabletsFor patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 10 mg/40 mg ezetimibe and simvastatin tablets when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Figure 1: Effect of interacting drugs on the pharmacokinetics of venlafaxine and active metabolite O-desmethylvenlafaxine (ODV).

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Factors	Dosage Adjustments for Aripiprazole
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors	Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double usual dose over 1 to 2 weeks

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DRUG	DESCRIPTION OF INTERACTION
Heparin	Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparin-treated patients.
Pyrazinamide	Inhibits pyrazinamide-induced hyperuricemia.
Uricosuric Agents	Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 2: Drug-Thyroidal Axis Interactions
	Drug or Drug Class		Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
		Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
		Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
		Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
		Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
		Amiodarone Iodide (including iodine- containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
	Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
	Drugs that may increase		Drugs that may decrease
	serum TBG concentration		serum TBG concentration
	Clofibrate		Androgens / Anabolic Steroids
	Estrogen-containing oral		Asparaginase
	contraceptives		Glucocorticoids
	Estrogens (oral)		Slow-Release Nicotinic Acid
	Heroin / Methadone
	5-Fluorouracil
	Mitotane
	Tamoxifen
	Drugs that may cause protein-binding site displacement
	Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)		Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
	Carbamazepine Hydantoins Phenobarbital Rifampin		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
	Drugs that may decrease T ₄ 5' - deiodinase activity
	Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)		Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, Ieading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
	Miscellaneous
	Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives		Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
	Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
	Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin		Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
	Cardiac Glycosides		Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
	Cytokines - Interferon-α - Interleukin-2		Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
	Growth Hormones - Somatrem - Somatropin		Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
	Ketamine		Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
	Methylxanthine Bronchodilators - (e.g., Theophylline)		Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
	Radiographic Agents		Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
	Sympathomimetics		Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
	Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics		These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Strong CYP3A4 Inhibitors
Clinical Impact:	Concomitant use of REXULTI with strong CYP3A4 inhibitors increased the exposure of brexpiprazole compared to the use of REXULTI alone [see Clinical Pharmacology (12.3)]
Intervention:	With concomitant use of REXULTI with a strong CYP3A4 inhibitor, reduce the REXULTI dosage [see Dosage and Administration (2.5)]
Examples:	itraconazole, clarithromycin, ketoconazole
Strong CYP2D6 Inhibitors*
Clinical Impact:	Concomitant use of REXULTI with strong CYP2D6 inhibitors increased the exposure of brexpiprazole compared to the use of REXULTI alone [see Clinical Pharmacology (12.3)]
Intervention:	With concomitant use of REXULTI with a strong CYP2D6 inhibitor, reduce the REXULTI dosage [see Dosage and Administration (2.5)]
Examples:	paroxetine, fluoxetine, quinidine
Both CYP3A4 Inhibitors and CYP2D6 Inhibitors
Clinical Impact:	Concomitant use of REXULTI with 1) a strong CYP3A4 inhibitor and a strong CYP2D6 inhibitor; or 2) a moderate CYP3A4 inhibitor and a strong CYP2D6 inhibitor; or 3) a strong CYP3A4 inhibitor and a moderate CYP2D6 inhibitor; or 4) a moderate CYP3A4 inhibitor and a moderate CYP2D6 inhibitor, increased the exposure of brexpiprazole compared to the use of REXULTI alone [see Clinical Pharmacology (12.3)]
Intervention:	With concomitant use of REXULTI with 1) a strong CYP3A4 inhibitor and a strong CYP2D6 inhibitor; or 2) a moderate CYP3A4 inhibitor and a strong CYP2D6 inhibitor; or 3) a strong CYP3A4 inhibitor and a moderate CYP2D6 inhibitor; or 4) a moderate CYP3A4 inhibitor and a moderate CYP2D6 inhibitor, decrease the REXULTI dosage [see Dosage and Administration (2.5)]
Examples:	1) itraconazole + quinidine 2) fluconazole + paroxetine 3) itraconazole + duloxetine 4) fluconazole + duloxetine
Strong CYP3A4 Inducers
Clinical Impact:	Concomitant use of REXULTI and a strong CYP3A4 inducer decreased the exposure of brexpiprazole compared to the use of REXULTI alone [see Clinical Pharmacology (12.3)]
Intervention:	With concomitant use of REXULTI with a strong CYP3A4 inducer, increase the REXULTI dosage [see Dosage and Administration (2.5)]
Examples:	rifampin, St. John’s wort

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T ₄ and T ₃levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT ₄ . Continued administration results in a decrease in serum T ₄ and normal FT ₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T ₄ and T ₃ to TBG and transthyretin. An initial increase in serum FT ₄ is followed by return of FT ₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T ₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T ₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T ₄ to T ₃, leading to decreased T ₃ levels. However, serum T ₄levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T ₃ and T ₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T ₃concentrations by 30% with minimal change in serum T ₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T ₃ and T ₄levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³ I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 7: Effect of Voriconazole on Pharmacokinetics of Other Drugs [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by Voriconazole)	Drug Plasma Exposure (C_max and AUC_τ)	Recommendations for Drug Dosage Adjustment/Comments
SirolimusResults based on in vivo clinical studies generally following repeat oral dosing with 200 mg BID voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Rifabutin (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (400 mg q24h)Results based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for at least 2 days voriconazole to healthy subjects (CYP3A4 Inhibition)	Significantly Increased	Contraindicated
Efavirenz (300 mg q24h) (CYP3A4 Inhibition)	Slight Increase in AUC_τ	When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)(CYP3A4 Inhibition) Low-dose Ritonavir (100 mg q12h)	No Significant Effect of Voriconazole on Ritonavir C_max or AUC_τ Slight Decrease in Ritonavir C_max and AUC_τ	Contraindicated because of significant reduction of voriconazole C_max and AUC_τ Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided (due to the reduction in voriconazole C_max and AUC_τ) unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Terfenadine, Astemizole, Cisapride, Pimozide, Quinidine (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated because of potential for QT prolongation and rare occurrence of torsade de pointes
Ergot Alkaloids (CYP450 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Contraindicated
Cyclosporine (CYP3A4 Inhibition)	AUC_τ Significantly Increased; No Significant Effect on C_max	When initiating therapy with voriconazole in patients already receiving cyclosporine, reduce the cyclosporine dose to one-half of the starting dose and follow with frequent monitoring of cyclosporine blood levels. Increased cyclosporine levels have been associated with nephrotoxicity. When voriconazole is discontinued, cyclosporine concentrations must be frequently monitored and the dose increased as necessary.
MethadoneResults based on in vivo clinical study following repeat oral dosing with 400 mg q12h for 1 day, then 200 mg q12h for 4 days voriconazole to subjects receiving a methadone maintenance dose (30–100 mg q24h) (CYP3A4 Inhibition)	Increased	Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during coadministration. Dose reduction of methadone may be needed
Fentanyl (CYP3A4 Inhibition)	Increased	Reduction in the dose of fentanyl and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7)]
Alfentanil (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of alfentanil and other opiates metabolized by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole. A longer period for monitoring respiratory and other opiate-associated adverse events may be necessary [see Drug Interactions (7)].
Oxycodone (CYP3A4 Inhibition)	Significantly Increased	Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 should be considered when coadministered with voriconazole. Extended and frequent monitoring for opiate-associated adverse events may be necessary [see Drug Interactions (7)].
NSAIDsNon-Steroidal Anti-Inflammatory Drug including. ibuprofen and diclofenac (CYP2C9 Inhibition)	Increased	Frequent monitoring for adverse events and toxicity related to NSAIDs. Dose reduction of NSAIDs may be needed [see Drug Interactions (7)].
Tacrolimus (CYP3A4 Inhibition)	Significantly Increased	When initiating therapy with voriconazole in patients already receiving tacrolimus, reduce the tacrolimus dose to one-third of the starting dose and follow with frequent monitoring of tacrolimus blood levels. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus concentrations must be frequently monitored and the dose increased as necessary.
Phenytoin (CYP2C9 Inhibition)	Significantly Increased	Frequent monitoring of phenytoin plasma concentrations and frequent monitoring of adverse effects related to phenytoin.
Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP3A4 Inhibition)	Increased	Monitoring for adverse events related to oral contraceptives is recommended during coadministration.
Warfarin (CYP2C9 Inhibition)	Prothrombin Time Significantly Increased	Monitor PT or other suitable anti-coagulation tests. Adjustment of warfarin dosage may be needed.
Omeprazole (CYP2C19/3A4 Inhibition)	Significantly Increased	When initiating therapy with voriconazole in patients already receiving omeprazole doses of 40 mg or greater, reduce the omeprazole dose by one-half. The metabolism of other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of other proton pump inhibitors.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects on Indinavir Exposure In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	No dosage adjustment for indinavir when coadministered with voriconazole Frequent monitoring for adverse events and toxicity related to other HIV protease inhibitors
Other NNRTIsNon-Nucleoside Reverse Transcriptase Inhibitors (CYP3A4 Inhibition)	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for Voriconazole to Inhibit Metabolism of Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to NNRTI
Benzodiazepines (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity (i.e., prolonged sedation) related to benzodiazepines metabolized by CYP3A4 (e.g., midazolam, triazolam, alprazolam). Adjustment of benzodiazepine dosage may be needed.
HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to statins. Increased statin concentrations in plasma have been associated with rhabdomyolysis. Adjustment of the statin dosage may be needed.
Dihydropyridine Calcium Channel Blockers (CYP3A4 Inhibition)	In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to calcium channel blockers. Adjustment of calcium channel blocker dosage may be needed.
Sulfonylurea Oral Hypoglycemics (CYP2C9 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring of blood glucose and for signs and symptoms of hypoglycemia. Adjustment of oral hypoglycemic drug dosage may be needed.
Vinca Alkaloids (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Frequent monitoring for adverse events and toxicity (i.e., neurotoxicity) related to vinca alkaloids. Adjustment of vinca alkaloid dosage may be needed.
Everolimus (CYP3A4 Inhibition)	Not Studied In Vivo or In Vitro, but Drug Plasma Exposure Likely to be Increased	Concomitant administration of voriconazole and everolimus is not recommended.

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitors (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs that Interfere with Hemostasis
Clinical Impact :	Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention :	Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see WARNINGS AND PRECAUTIONS ( 5 . 11 )].
Aspirin
Clinical Impact :	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see WARNINGS AND PRECAUTIONS ( 5 . 2 )].
Intervention :	Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see WARNINGS AND PRECAUTIONS ( 5 . 11 )]. Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors , Angiotensin Receptor Blockers , or Beta - Blockers
Clinical Impact :	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention :	During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see WARNINGS AND PRECAUTIONS ( 5 . 6 )]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact :	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention :	During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see WARNINGS AND PRECAUTIONS ( 5 . 6 )].
Lithium
Clinical Impact :	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [ see CLINICAL PHARMACOLOGY ( 12 . 3 )].
Intervention :	During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact :	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention :	During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact :	Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention :	During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact :	Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see WARNINGS AND PRECAUTIONS ( 5 . 2 )].
Intervention :	The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact :	Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention :	During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide Is not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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edema
hereditary coumarin resistance
hyperlipemia

hypothyroidism
nephrotic syndrome

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Table 4 Other Potentially Significant Drug Interactions
Concomitant Drug Class or Food	Noted or anticipated Outcome	Clinical Comment
HMG-Co A Reductase Inhibitors: atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin	Pharmacokinetic and/or pharmacodynamic interaction: the addition of one drug to a stable long-term regimen of the other has resulted in myopathy and rhabdomyolysis (including a fatality)	Weigh the potential benefits and risks and carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during initial therapy; monitoring CPK (creatine phosphokinase) will not necessarily prevent the occurrence of severe myopathy.
Other Lipid Lowering Drugs: fibrates, gemfibrozil
Digitalis Glycosides: digoxin	P-gp substrate; rhabdomyolysis has been reported

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Table 4. Mean (95% C.I.) maximal change in baseline in systolic blood pressure (mmHg) following vardenafil 10 and 20 mg in healthy volunteers on daily alpha-blocker therapy
		Dosing of Vardenafil and Alpha-Blocker Separated by 6 Hours		Simultaneous dosing of Vardenafil and Alpha-Blocker
Alpha-Blocker		Vardenafil 10 mg Placebo-Subtracted	Vardenafil 20 mg Placebo-Subtracted	Vardenafil 10 mg Placebo-Subtracted	Vardenafil 20 mg Placebo-Subtracted
Terazosin 10 mg daily	Standing SBP	-7 (-10, -3)	-11 (-14, -7)	-23 (-31, 16) Due to the sample size, confidence intervals may not be an accurate measure for these data. These values represent the range for the difference.	-14 (-33, 11)
Terazosin 10 mg daily	Supine SBP	-5 (-8, -2)	-7 (-11, -4)	-7 (-25, 19)	-7 (-31, 22)
Tamsulosin 0.4 mg daily	Standing SBP	-4 (-8, -1)	-8 (-11, -4)	-8 (-14, -2)	-8 (-14, -1)
	Supine SBP	-4 (-8, 0)	-7 (-11, -3)	-5 (-9, -2)	-3 (-7, 0)

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Table 8: Clinically Significant Drug Interactions with Clarithromycin
Drugs That Are Affected By Clarithromycin
Drug(s) with Pharmacokinetics Affected by Clarithromycin		Recommendation	Comments
Antiarrhythmics: Disopyramide Quinidine Dofetilide Amiodarone Sotalol Procainamide Digoxin		Not Recommended Use With Caution	Disopyramide, Quinidine: There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs [see Warnings and Precautions (5.3)] . Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine. There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide. Digoxin: Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are co-administered, inhibition of Pgp by clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range.
Oral Anticoagulants: Warfarin		Use With Caution	Oral anticoagulants: Spontaneous reports in the postmarketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously [see Warnings and Precautions (5.4)] .
Antiepileptics: Carbamazepine		Use With Caution	Carbamazepine: Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered. Increased serum concentrations of carbamazepine were observed in clinical trials with clarithromycin. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with carbamazepine.
Antifungals: Itraconazole Fluconazole		Use With Caution No Dose Adjustment	Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly (see also Itraconazole under “Drugs That Affect Clarithromycin” in the table below). Clarithromycin may increase the plasma concentrations of itraconazole. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions. Fluconazole: [see Pharmacokinetics (12.3)]
Anti-Gout Agents: Colchicine (in patients with renal or hepatic impairment) Colchicine (in patients with normal renal and hepatic function)		Contraindicated Use With Caution	Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. The dose of colchicine should be reduced when co-administered with clarithromycin in patients with normal renal and hepatic function [see Contraindications (4.4) and Warnings and Precautions (5.4)] .
Antipsychotics: Pimozide Quetiapine		Contraindicated	Pimozide: [See Contraindications (4.2)] Quetiapine: Quetiapine is a substrate for CYP3A4, which is inhibited by clarithromycin. Co-administration with clarithromycin could result in increased quetiapine exposure and possible quetiapine related toxicities. There have been postmarketing reports of somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation during concomitant administration. Refer to quetiapine prescribing information for recommendations on dose reduction if co-administered with CYP3A4 inhibitors such as clarithromycin.
Antispasmodics: Tolterodine (patients deficient in CYP2D6 activity)		Use With Caution	Tolterodine: The primary route of metabolism for tolterodine is via. CYP2D6. However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via. CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when co-administered with clarithromycin.
Antivirals: Atazanavir Saquinavir (in patients with decreased renal function) Ritonavir Etravirine Maraviroc Boceprevir (in patients with normal renal function) Didanosine Zidovudine		Use With Caution No Dose Adjustment	Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)] . Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction (see Saquinavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)] . Ritonavir, Etravirine: (see Ritonavir and Etravirine under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)] . Maraviroc : Clarithromycin may result in increases in maraviroc exposures by inhibition of CYP3A metabolism. See Selzentry ^® prescribing information for dose recommendation when given with strong CYP3A inhibitors such as clarithromycin. Boceprevir: Both clarithromycin and boceprevir are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when co-administered. No dose adjustments are necessary for patients with normal renal function (see Victrelis ^® prescribing information). Zidovudine: Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Administration of clarithromycin and zidovudine should be separated by at least two hours [see Pharmacokinetics (12.3)] .
Calcium Channel Blockers: Verapamil Amlodipine Diltiazem Nifedipine		Use With Caution	Verapamil: Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, [see Warnings and Precautions (5.4)] . Amlodipine, Diltiazem: [See Warnings and Precautions (5.4)] Nifedipine: Nifedipine is a substrate for CYP3A. Clarithromycin and other macrolides are known to inhibit CYP3A. There is potential of CYP3A-mediated interaction between nifedipine and clarithromycin. Hypotension and peripheral edema were observed when clarithromycin was taken concomitantly with nifedipine [see Warnings and Precautions (5.4)] .
Ergot Alkaloids: Ergotamine Dihydroergotamine		Contraindicated	Ergotamine, Dihydroergotamine: Postmarketing reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4.6)].
Gastroprokinetic Agents: Cisapride		Contraindicated	Cisapride: [See Contraindications (4.2)]
HMG-CoA Reductase Inhibitors: Lovastatin Simvastatin Atorvastatin Pravastatin Fluvastatin		Contraindicated Use With Caution No Dose Adjustment	Lovastatin, Simvastatin, Atorvastatin, Pravastatin, Fluvastatin: [See Contraindications (4.5) and Warnings and Precautions (5.4)]
Hypoglycemic Agents: Nateglinide Pioglitazone Repaglinide Rosiglitazone Insulin		Use With Caution	Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)] Insulin: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]
Immunosuppressants: Cyclosporine Tacrolimus		Use With Caution	Cyclosporine: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine. Tacrolimus: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with tacrolimus.
Phosphodiesterase inhibitors: Sildenafil Tadalafil Vardenafil		Use With Caution	Sildenafil, Tadalafil, Vardenafil: Each of these phosphodiesterase inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant administration of clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil, or vardenafil will result in increased exposure of these phosphodiesterase inhibitors. Co-administration of these phosphodiesterase inhibitors with clarithromycin is not recommended. Increased systemic exposure of these drugs may occur with clarithromycin; reduction of dosage for phosphodiesterase inhibitors should be considered (see their respective prescribing information).
Proton Pump Inhibitors: Omeprazole		No Dose Adjustment	Omeprazole: The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when coadministered with clarithromycin as a result of increased omeprazole exposures [see Pharmacokinetics (12.3)] (see also Omeprazole under “Drugs That Affect Clarithromycin” in the table below).
Xanthine Derivatives: Theophylline		Use With Caution	Theophylline: Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations [see Pharmacokinetics (12.3)] . Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range.
Triazolobenzodiazepines and Other Related Benzodiazepines: Midazolam Alprazolam Triazolam Temazepam Nitrazepam Lorazepam		Use With Caution No Dose Adjustment	Midazolam: When oral midazolam is co-administered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated [see Warnings and Precautions (5.4) and Pharmacokinetics (12.3)] . Triazolam, Alprazolam: Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is co-administered with clarithromycin. There have been postmarketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested. In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines. Temazepam, Nitrazepam, Lorazepam: For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.
Cytochrome P450 Inducers: Rifabutin		Use With Caution	Rifabutin: Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis (see Rifabutin under “Drugs That Affect Clarithromycin” in the table below).
Other Drugs Metabolized by CYP3A: Alfentanil Bromocriptine Cilostazol Methylprednisole Vinblastine Phenobarbital St. John’s Wort		Use With Caution	There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort.
Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A: Hexobarbital Phenytoin Valproate		Use With Caution	There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.
Drugs that Affect Clarithromycin
Drug(s) that Affect the Pharmacokinetics of Clarithromycin	Recommendation		Comments
Antifungals: Itraconazole	Use With Caution		Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions (see also Itraconazole under “Drugs That Are Affected By Clarithromycin” in the table above).
Antivirals: Atazanavir Ritonavir (in patients with decreased renal function) Saquinavir (in patients with decreased renal function) Etravirine Saquinavir (in patients with normal renal function) Ritonavir (in patients with normal renal function)	Use With Caution No Dose Adjustment		Atazanavir: When clarithromycin is co-administered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology (12.3)] . Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors. Ritonavir: Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with ritonavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium [see Pharmacokinetics (12.3)] . Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors. Saquinavir: When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (refer to ritonavir above) [see Pharmacokinetics (12.3)] . Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.
Proton Pump Inhibitors: Omeprazole	Use With Caution		Omeprazole: Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole [see Pharmacokinetics (12.3)] .
Miscellaneous Cytochrome P450 Inducers: Efavirenz Nevirapine Rifampicin Rifabutin Rifapentine	Use With Caution		Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are Affected By Clarithromycin” in the table above).

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
	? CBZ epoxide	May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

Table 3: Clinically Relevant Interactions Affecting Drugs Co-Administered with Omeprazole and Interaction with Diagnostics
Antiretrovirals
Clinical Impact:	The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
Intervention:	Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications (4)]. Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:	Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention:	Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact:	Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].
Intervention:	A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact:	Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)]. There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention:	Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6)].
Citalopram
Clinical Impact:	Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention:	Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:	Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].
Intervention:	Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:	Potential for increased exposure of phenytoin.
Intervention:	Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:	Increased exposure of diazepam [see Clinical Pharmacology (12.3)].
Intervention:	Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:	Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention:	Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:	Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:	Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)]. See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:	Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:	See Contraindications, Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact:	Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention:	Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:	Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10), Clinical Pharmacology (12.2)].
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:	Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact:	There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:	An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:	There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:	Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.

Table name:

Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of aripiprazole with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)] .	With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)] .
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)] .	With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)] .
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.8)] .
Benzodiazepines(e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.8)] .	Monitor sedation and blood pressure. Adjust dose accordingly.

Table name:

^a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. ^b = Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. NE = Not Evaluated
AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

Table name:

Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin	Monitor phenytoin level (7)
Methotrexate	Monitor for methotrexate toxicity (7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin (7)

Table 3: Clinically Relevant Interactions Affecting Drugs Co-Administered with Omeprazole and Interaction with Diagnostics
Antiretrovirals
Clinical Impact:	The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
Intervention:	Rilpivirine-containing products: Concomitant use with omeprazole is contraindicated [see Contraindications (4)]. Atazanavir: Avoid concomitant use with omeprazole. See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with omeprazole. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Warfarin
Clinical Impact:	Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
Intervention:	Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.
Methotrexate
Clinical Impact:	Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11)].
Intervention:	A temporary withdrawal of omeprazole may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact:	Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)]. There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention:	Avoid concomitant use with omeprazole. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.6)].
Citalopram
Clinical Impact:	Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention:	Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact:	Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].
Intervention:	Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact:	Potential for increased exposure of phenytoin.
Intervention:	Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact:	Increased exposure of diazepam [see Clinical Pharmacology (12.3)].
Intervention:	Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Digoxin
Clinical Impact:	Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].
Intervention:	Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact:	Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention:	Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)]. See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and Amoxicillin
Clinical Impact:	Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Intervention:	See Contraindications, Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.
Tacrolimus
Clinical Impact:	Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention:	Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact:	Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.10), Clinical Pharmacology (12.2)].
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Impact:	Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention:	Temporarily stop omeprazole treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact:	There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs.
Intervention:	An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact:	There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).
Intervention:	Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with omeprazole.

Table name:

Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptivepreparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

Table name:

NA – Not available/reported
Digoxin concentrations increased greater than 50%
	Digoxin Serum Concentration Increase	Digoxin AUC Increase	Recommendations
Amiodarone	70%	NA	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
Captopril	58%	39%
Clarithromycin	NA	70%
Dronedarone	NA	150%
Gentamicin	129-212%	NA
Erythromycin	100%	NA
Itraconazole	80%	NA
Nitrendipine	57%	15%
Propafenone	NA	60-270%
Quinidine	100%	NA
Ranolazine	50%	NA
Ritonavir	NA	86%
Tetracycline	100%	NA
Verapamil	50-75%	NA
Digoxin concentrations increased less than 50%
Atorvastatin	22%	15%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
Carvedilol	16%	14%
Diltiazem	20%	NA
Indomethacin	40%	NA
Nefazodone	27%	15%
Nifedipine	45%	NA
Propantheline	24%	24%
Quinine	NA	33%
Saquinavir	27%	49%
Spironolactone	25%	NA
Telmisartan	20-49%	NA
Tolvaptan	30%	NA
Trimethoprim	22-28%	NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole, rabeprazole,			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate, sulfasalazine			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20-40% as necessary.
No significant Digoxin exposure changes
Please refer to section 12 for a complete list of drugs which were studied but reported no significant changes on digoxin exposure.			No additional actions are required.

Table name:

Table 2: Drug-Thyroidal Axis Interactions
	Drug or Drug Class		Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
		Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
		Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
		Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
		Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
		Amiodarone Iodide (including iodine- containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
	Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
	Drugs that may increase		Drugs that may decrease
	serum TBG concentration		serum TBG concentration
	Clofibrate		Androgens / Anabolic Steroids
	Estrogen-containing oral		Asparaginase
	contraceptives		Glucocorticoids
	Estrogens (oral)		Slow-Release Nicotinic Acid
	Heroin / Methadone
	5-Fluorouracil
	Mitotane
	Tamoxifen
	Drugs that may cause protein-binding site displacement
	Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)		Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
	Carbamazepine Hydantoins Phenobarbital Rifampin		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
	Drugs that may decrease T ₄ 5' - deiodinase activity
	Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)		Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, Ieading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
	Miscellaneous
	Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives		Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
	Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
	Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin		Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
	Cardiac Glycosides		Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
	Cytokines - Interferon-α - Interleukin-2		Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
	Growth Hormones - Somatrem - Somatropin		Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
	Ketamine		Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
	Methylxanthine Bronchodilators - (e.g., Theophylline)		Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
	Radiographic Agents		Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
	Sympathomimetics		Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
	Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics		These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name:

Factors	Dosage Adjustment of ABILIFY
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors	Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double usual dose over 1 to 2 weeks

Table name:

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir )	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir)	Do not exceed 40 mg atorvastatin daily
Hepatitis C Protease inhibitor (boceprevir)

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AED Co-administered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increase^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease
^a= Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin. ^b = Is not administered but is an active metabolite of carbamazepine. NC = Less than 10% change in plasma concentration. NE = Not Evaluated

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Antibiotics	Anticonvulsants	Other Drugs / Dietary Supplements
nafcillin	carbamazepine	bosentan	St. John’s Wort
rifampin	oxcarbazepine	octreotide
	phenobarbital	orlistat
	phenytoin	sulfinpyrazone
		terbinafine
		ticlopidine

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin Tablets, USP
Drug(s)	Recommendation		Comments
Tizanidine	Contraindicated		Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications ( 4.2 )]
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)		Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate. [See Warnings and Precautions ( 5.6 ).]
Drugs Known to Prolong QT Interval	Avoid Use		Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions ( 5.10 ) and Use in Specific Populations ( 8.5 )].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated		Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [See Adverse Reactions (6.1).]
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)		To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)		Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)		The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels		Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution		Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine	Use with caution		Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs	Use with caution		Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution Two-fold increase in exposure		Monitor for sildenafil toxicity (see Pharmacokinetics 12.3).
Duloxetine	Avoid Use Five-fold increase in duloxetine exposure		If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life		Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin Tablets, USP
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)		Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration. ( 2 )].		Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid		Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)		Potentiation of ciprofloxacin toxicity may occur.

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 13. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation).
↑ = Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of this product. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet or oral solution formulation is taken within 2 hours of these products. Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4 , 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.12 , 7.3)

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( 7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( 7)
Phenytoin	Monitor phenytoin level ( 7)
Methotrexate	Monitor for methotrexate toxicity ( 7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine ( 7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin ( 7)

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Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Figure 2: Effect of venlafaxine on the pharmacokinetics interacting drugs and their active metabolites.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
↓= Decreased (induces lamotrigine gluronidation). ↑= Increased (inhibits lamotrigine glucuronidation). ?= Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
	? CBZ epoxide	May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug ( s )	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see CONTRAINDICATIONS (4.2)]
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see WARNINGS AND PRECAUTIONS (5.9)].
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see WARNINGS AND PRECAUTIONS (5.11) and USE IN SPECIFIC POPULATIONS (8.5)].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs [see ADVERSE REACTIONS (6.1)].
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co- administration with ciprofloxacin [see WARNINGS AND PRECAUTIONS (5.16)].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution Two-fold increase in exposure	Monitor for sildenafil toxicity [see CLINICAL PHARMACOLOGY 12.3].
Duloxetine	Avoid Use Five-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug ( s ) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx^® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation- containing products administration [see DOSAGE AND ADMINISTRATION (2.4)].	Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

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Table 6. Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interactions [see Dosage and Administration (2)]
Concomitant Drug Class: Drug Name	Effect on Concentration of Dolutegravir and/or Concomitant Drug	Clinical Comment
HIV-1 Antiviral Agents
Non-nucleoside reverse transcriptase inhibitor: Etravirine ^a	↓Dolutegravir	Use of TIVICAY with etravirine without coadministration of atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir is not recommended.
Non-nucleoside reverse transcriptase inhibitor: Efavirenz ^a	↓Dolutegravir	Adjust dose of TIVICAY to 50 mg twice daily for treatment-naïve and treatment-experienced, INSTI-naïve adult patients. In pediatric patients, increase the weight-based dose to twice daily (Table 2). Use alternative combinations that do not include metabolic inducers where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance. ^b
Non-nucleoside reverse transcriptase inhibitor: Nevirapine	↓Dolutegravir	Avoid coadministration with nevirapine because there are insufficient data to make dosing recommendations.
Protease inhibitor: Fosamprenavir/ritonavir ^a Tipranavir/ritonavir ^a	↓Dolutegravir	Adjust dose of TIVICAY to 50 mg twice daily for treatment-naïve and treatment-experienced, INSTI-naïve adult patients. In pediatric patients, increase the weight-based dose to twice daily (Table 2). Use alternative combinations that do not include metabolic inducers where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance. ^b
Other Agents
Carbamazepine ^a	↓Dolutegravir	Adjust dose of TIVICAY to 50 mg twice daily in treatment-naïve or treatment-experienced, INSTI-naïve adult patients. In pediatric patients, increase the weight-based dose to twice daily (Table 2). Use alternative treatment that does not include carbamazepine where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance. ^b
Oxcarbazepine Phenytoin Phenobarbital St. John’s wort ( Hypericum perforatum)	↓Dolutegravir	Avoid coadministration with TIVICAY because there are insufficient data to make dosing recommendations.
Medications containing polyvalent cations (e.g., Mg or Al): Cation-containing antacids ^a or laxatives Sucralfate Buffered medications	↓Dolutegravir	Administer TIVICAY 2 hours before or 6 hours after taking medications containing polyvalent cations.
Oral calcium or iron supplements, including multivitamins containing calcium or iron ^a	↓Dolutegravir	Administer TIVICAY 2 hours before or 6 hours after taking supplements containing calcium or iron. Alternatively, TIVICAY and supplements containing calcium or iron can be taken together with food.
Metformin	↑Metformin	With concomitant use, limit the total daily dose of metformin to 1,000 mg either when starting metformin or TIVICAY. When stopping TIVICAY, the metformin dose may require an adjustment. Monitoring of blood glucose when initiating concomitant use and after withdrawal of TIVICAY is recommended.
Rifampin ^a	↓Dolutegravir	Adjust dose of TIVICAY to 50 mg twice daily for treatment-naïve and treatment-experienced, INSTI-naïve adult patients. In pediatric patients, increase the weight-based dose to twice daily (Table 2). Use alternatives to rifampin where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance. ^b

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Inhibitors of CYP2D6
Clinical Impact:		The concomitant use of tramadol hydrochloride and acetaminophen and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride and acetaminophen is achieved. Since M1 is a more potent µ-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease and the M1 plasma concentration will increase which could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, and may cause potentially fatal respiratory depression [see Clinical Pharmacology (12.3)].
Intervention:		If concomitant use of a CYP2D6 inhibitor is necessary, follow patients closely for adverse reactions including opioid withdrawal, seizures and serotonin syndrome. If a CYP2D6 inhibitor is discontinued, consider lowering tramadol hydrochloride and acetaminophen dosage until stable drug effects are achieved. Follow patients closely for adverse events including respiratory depression and sedation.
Examples		Quinidine, fluoxetine, paroxetine and bupropion
Inhibitors of CYP3A4
Clinical Impact:		The concomitant use of tramadol hydrochloride and acetaminophen and CYP3A4 inhibitors can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1. Follow patients closely for increased risk of serious adverse events including seizures and serotonin syndrome, and adverse reactions related to opioid toxicity including potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of tramadol hydrochloride and acetaminophen is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy and possibly signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol.
Intervention:		If concomitant use is necessary, consider dosage reduction of tramadol hydrochloride and acetaminophen until stable drug effects are achieved. Follow patients closely for seizures and serotonin syndrome, and signs of respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the tramadol hydrochloride and acetaminophen dosage until stable drug effects are achieved and follow patients for signs and symptoms of opioid withdrawal.
Examples		Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact:		The concomitant use of tramadol hydrochloride and acetaminophen and CYP3A4 inducers can decrease the plasma concentration of tramadol [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression, seizures and serotonin syndrome.
Intervention:		If concomitant use is necessary, consider increasing the tramadol hydrochloride and acetaminophen dosage until stable drug effects are achieved. Follow patients for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider tramadol hydrochloride and acetaminophen dosage reduction and monitor for seizures and serotonin syndrome, and signs of sedation and respiratory depression. Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of tramadol hydrochloride, acetaminophen and carbamazepine is not recommended.
Examples:		Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:		Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:		Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.6)].
Examples:		Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:		The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:		If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue tramadol hydrochloride and acetaminophen if serotonin syndrome is suspected.
Examples:		Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:		MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.7)] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
Intervention:		Do not use tramadol hydrochloride and acetaminophen in patients taking MAOIs or within 14 days of stopping such treatment.
Examples:		phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:		May reduce the analgesic effect of tramadol hydrochloride and acetaminophen and/or precipitate withdrawal symptoms.
Intervention:		Avoid concomitant use.
Examples:		butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:		Tramadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:		Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of tramadol hydrochloride and acetaminophen and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:		Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:		Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:		The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:		Monitor patients for signs of urinary retention or reduced gastric motility when tramadol hydrochloride and acetaminophen is used concomitantly with anticholinergic drugs.
Digoxin
Clinical Impact:		Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity.
Intervention:		Follow patients for signs of digoxin toxicity and adjust dosage of digoxin as needed.
Warfarin
Clinical Impact:		Post-marketing surveillance of tramadol has revealed rare reports of alteration of warfarin effect, including elevation of prothrombin times.
Intervention:		Monitor the prothrombin time of patients on warfarin for signs of an interaction and adjust the dosage of warfarin as needed.

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Antibiotics	Anticonvulsants	Other Drugs/Dietary Supplements
nafcillin	carbamazepine	bosentan
rifampin	oxcarbazepine	octreotide
	phenobarbital	orlistat
	phenytoin	sulfinpyrazone
		St. John's Wort
		terbinafine
		ticlopidine

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Interacting DrugInteracting Drug	InteractionInteraction
Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products.
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding ( 7.2)
Antidiabetic agents	Carefully monitor blood glucose ( 5.11, 7.3)

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T and T levels and increase TSH, although all values remain within normal limits in most patients. ₄ ₃
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT . Continued administration results in a decrease in serum T and normal FT and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T and T to TBG and transthyretin. An initial increase in serum FT , is followed by return of FT to normal levels with sustained therapeutic serum salicylate concentrations, although total-T levels may decrease by as much as 30%. ₄ ₄ ₄ ₄ ₃ ₄ ₄ ₄
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid. ₄
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T to T , leading to decreased T levels. However, serum T levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T and T levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T concentrations by 30% with minimal change in serum T levels. However, long-term glucocorticoid therapy may result in slightly decreased T and T levels due to decreased TBG production (see above). ₄ ₃ ₃ ₄ ₃ ₄ ₃ ₄ ₃ ₄
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of I, I, and Tc. ¹²³ ¹³¹ ^99m
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 23: Clinically Important Drug Interactions with Aripiprazole:
Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [ see CLINICAL PHARMACOLOGY ( 12 . 3 )].	With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [ see DOSAGE AND ADMINISTRATION ( 2 . 7 )].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [ see CLINICAL PHARMACOLOGY ( 12 . 3 )].	With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [ see DOSAGE AND ADMINISTRATION ( 2 . 7 )].
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [ see WARNINGS AND PRECAUTIONS ( 5 . 7 )].
Benzodiazepines (e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepamalone [ see WARNINGS AND PRECAUTIONS ( 5 . 7 )]	Monitor sedation and blood pressure. Adjust dose accordingly.

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Table 5. Clinically-Significant Drug Interactions with Sertraline Hydrochloride
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	The concomitant use of SSRIs including sertraline hydrochloride and MAOIs increases the risk of serotonin syndrome.
Intervention:	Sertraline hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [See Dosage and Administration (2.5), Contraindications (4), Warnings and Precautions (5.2)].
Examples:	selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
Pimozide
Clinical Impact:	Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QT prolongation and ventricular arrhythmias.
Intervention:	Concomitant use of pimozide and sertraline hydrochloride is contraindicated [See Contraindications (4)].
Other Serotonergic Drugs
Clinical Impact:	The concomitant use of serotonergic drugs with sertraline hydrochloride increases the risk of serotonin syndrome.
Intervention:	Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of sertraline hydrochloride and/or concomitant serotonergic drugs [See Warnings and Precautions (5.2)].
Examples:	other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort
Drugs that Interfere with Hemostasis (antiplatelet agents and anticoagulants)
Clinical Impact:	The concurrent use of an antiplatelet agent or anticoagulant with sertraline hydrochloride may potentiate the risk of bleeding.
Intervention:	Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [See Warnings and Precautions (5.3)].
Examples:	aspirin, clopidogrel, heparin, warfarin
Drugs Highly Bound to Plasma Protein
Clinical Impact:	Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of sertraline hydrochloride with another drug that is highly bound to plasma protein may increase free concentrations of sertraline hydrochloride or other tightly-bound drugs in plasma [See Clinical Pharmacology (12.3)].
Intervention:	Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs as warranted.
Examples:	warfarin
Drugs Metabolized by CYP2D6
Clinical Impact:	Sertraline hydrochloride is a CYP2D6 inhibitor [See Clinical Pharmacology (12.3)]. The concomitant use of sertraline hydrochloride with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate.
Intervention:	Decrease the dosage of a CYP2D6 substrate if needed with concomitant sertraline hydrochloride use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride is discontinued.
Examples:	propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine
Phenytoin
Clinical Impact:	Phenytoin is a narrow therapeutic index drug. Sertraline hydrochloride may increase phenytoin concentrations.
Intervention:	Monitor phenytoin levels when initiating or titrating sertraline hydrochloride. Reduce phenytoin dosage if needed.
Examples:	phenytoin, fosphenytoin

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Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine concentrations approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine and carbamazepine epoxide	? carbamazepine epoxide	May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Table 5: Established Drug Interactions Based on Studies with Didanosine Delayed-Release Capsules or Studies with Buffered Formulations of Didanosine and Expected to Occur with Didanosine Delayed-Release Capsules
↑ Indicates increase. ↓ Indicates decrease.
Drug	Effect	Clinical Comment
ganciclovir	↑didanosine concentration	If there is no suitable alternative to ganciclovir, then use in combination with didanosine delayed-release capsules with caution. Monitor for didanosine-associated toxicity.
methadone	↓didanosine concentration	If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is didanosine delayed-release capsules. Patients should be closely monitored for adequate clinical response when didanosine delayed-release capsules are coadministered with methadone, including monitoring for changes in HIV RNA viral load. Do not coadminister methadone with didanosine pediatric powder due to significant decreases in didanosine concentrations.
nelfinavir	No interaction 1 hour after didanosine	Administer nelfinavir 1 hour after didanosine delayed-release capsules.
tenofovir disoproxilfumarate	↑didanosine concentration	A dose reduction of didanosine delayed-release capsules to the following dosage once daily taken together with tenofovir disoproxil fumarate and a light meal (400 kcalories or less and 20% fat or less ) or in the fasted state is recommended. 250 mg (adults weighing at least 60 kg with creatinine clearance of at least 60 mL/min) 200 mg (adults weighing less than 60 kg with creatinine clearance of at least 60 mL/min) Patients should be monitored for didanosine-associated toxicities and clinical response.

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Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs that Interfere with Hemostasis
Clinical Impact :	Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention :	Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions ( 5 . 11)].
Aspirin
Clinical Impact :	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions ( 5 . 2)].
Intervention :	Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions ( 5 . 11)]. Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors , Angiotensin Receptor Blockers , or Beta - Blockers
Clinical Impact :	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention :	During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions ( 5 . 6 )]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact :	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention :	During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see Warnings and Precautions ( 5 . 6)].
Lithium
Clinical Impact :	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [ see Clinical Pharmacology ( 12 . 3)].
Intervention :	During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact :	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention :	During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact :	Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention :	During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact :	Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions ( 5 . 2)].
Intervention :	The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact :	Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention :	During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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AED Coadministered	AED Concentration	Topiramate Concentration
Phenytoin	NC or 25% increasePlasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxideIs not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( 7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( 7)
Phenytoin	Monitor phenytoin level ( 7)
Methotrexate	Monitor for methotrexate toxicity ( 7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine ( 7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin ( 7)

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Classes of Drugs
also: diet high in vitamin K unreliable PT/INR determinations
Adrenal Cortical Steroid Inhibitors	Antipsychotic Medications	Hypolipidemics^†
Antacids	Antithyroid Drugs^†	Bile Acid-Binding Resins^†
Antianxiety Agents Antiarrhythmics^†	Barbiturates Diuretics^†	HMG-CoA Reductase Inhibitors^†
Anticonvulsants^†	Enteral Nutritional Supplements	Immunosuppressives
Antidepressants^†	Fungal Medications, Systemic^†	Oral Contraceptives,
Antihistamines	Gastric Acidity and Peptic Ulcer Agents^†	Estrogen Containing
Antineoplastics^†	Hypnotics^†	Selective Estrogen Receptor Modulators
		Steroids, Adrenocortical^†
		Tuberculosis Agents^† Vitamins^†
Specific Drugs Reported:
alcoholIncreased and decreased PT/INR responses have been reported.	warfarin sodium underdosage	phenytoin
aminoglutethimide	cyclophosphamide	pravastatin
amobarbital	dicloxacillin	prednisone
atorvastatin	ethchlorvynol	primidone
azathioprine	glutethimide	propylthiouracil
butabarbital	griseofulvin	raloxifene
butalbital	haloperidol	ranitidine
carbamazepine	meprobamate	rifampin
chloral hydrate	6-mercaptopurine	secobarbital
chlordiazepoxide	methimazole	spironolactone
chlorthalidone	moricizine hydrochloride	sucralfate
cholestyramine	nafcillin	trazodone
clozapine	paraldehyde	vitamin C (high dose)
corticotropin	pentobarbital	vitamin K
cortisone	phenobarbital

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7.1, 7.2, 7.3, 7.4)
Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine, danazol	Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Diltiazem	Do not exceed 40 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Drug	Description
Heparin	Salicylate decreases platelet adhesivesness and interferes with hemostasis in heparin-treated patients
Pyrazinamide	Inhibits pyrazinamide-induced hyperuricemia
Uricosuric Agents	Effect of probenecid, sulfinpyrazone and phenylbutazone inhibited

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, gemfibrozil, cyclosporine,danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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Table 13. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation). ↑ = Increased (inhibits lamotrigine glucuronidation). ? = Conflicting data.
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Table 25: Clinically Important Drug Interactions with Aripiprazole:
Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION(2.7 )].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3 )].	With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION(2.7 )].
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.8 )].
Benzodiazepines (e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepamalone [see WARNINGS AND PRECAUTIONS (5.7)]	Monitor sedation and blood pressure. Adjust dose accordingly.

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Bleeding times
Clinical Impact:	Naproxen may decrease platelet aggregation and prolong bleeding time.
Intervention:	This effect should be kept in mind when bleeding times are determined.
Porter-Silber test
Clinical Impact:	The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay.
Intervention:	Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.
Urinary assays of 5-hydroxy indoleacetic acid (5HIAA)
Clinical Impact:	Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Intervention:	This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined.

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Calcium Channel	Antifungals	Antibiotics	Glucocorticoids		Other Drugs
Blockers	fluconazole	azithromycin		methylprednisolone	allopurinol
diltiazem	itraconazole	clarithromycin			amiodarone
nicardipine	ketoconazole	erythromycin			bromocriptine
verapamil		quinupristin/			colchicine
	voriconazole	dalfopristin
					danazol
					imatinib
					metoclopramide
					nefazodone
					oral contraceptives

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Table 4: Clinically Relevant Interactions Affecting Omeprazole When Co-Administered with Other Drugs
CYP2C19 or CYP3A4 Inducers
Clinical Impact:	Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention:	St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions (5.9)]. Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:	Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
Intervention:	Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole.

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Table 2: Clinically Significant Drug Interactions with Sufentanil Citrate Injection
Inhibitors of CYP3A4
Clinical Impact:	The concomitant use of Sufentanil Citrate Injection and CYP3A4 inhibitors can increase the plasma concentration of sufentanil, resulting in increased or prolonged opioid effects, particularly when an inhibitor is added after a stable dose of Sufentanil Citrate Injection is achieved [see Warnings and Precautions (5.4)]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the sufentanil plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to sufentanil.
Intervention:	If concomitant use is necessary, consider dosage reduction of Sufentanil Citrate Injection until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the Sufentanil Citrate Injection dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples:	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir), grapefruit juice
CYP3A4 Inducers
Clinical Impact:	The concomitant use of Sufentanil Citrate Injection and CYP3A4 inducers can decrease the plasma concentration of sufentanil [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to sufentanil [see Warnings and Precautions (5.4)]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the sufentanil plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention:	If concomitant use is necessary, consider increasing the Sufentanil Citrate Injection dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider Sufentanil Citrate Injection dosage reduction and monitor for signs of respiratory depression.
Examples:	Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	The concomitant use of Sufentanil Citrate Injection with CNS depressants my result in decreased pulmonary artery pressure and may cause hypotension. Even small dosages of diazepam may cause cardiovascular depression when added to high dose or anesthetic dosages of Sufentanil Citrate Injection. As postoperative analgesia, concomitant use of Sufentanil Citrate Injection can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	As postoperative analgesia, start with a lower dose of Sufentanil Citrate Injection and monitor patients for signs of respiratory depression, sedation, and hypotension. Fluids or other measures to counter hypotension should be available. [see Warnings and Precautions (5.5)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions 5.5].
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Sufentanil Citrate Injection if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
Intervention:	The use of Sufentanil Citrate Injection is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of Sufentanil Citrate Injection and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Sufentanil may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Sufentanil Citrate Injection and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when Sufentanil Citrate Injection is used concomitantly with anticholinergic drugs.
Nitrous oxide
Clinical Impact:	Nitrous oxide has been reported to produce cardiovascular depression when given with higher doses of Sufentanil Citrate Injection.
Intervention:	Monitor patients for signs of cardiovascular depression that may be greater than otherwise expected.

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Table 6: Predicted Drug Interactions with Didanosine
↑ Indicates increase.
Drug or Drug Class	Effect	Clinical Comment
Drugs that may cause pancreatic toxicity	↑risk of pancreatitis	Use only with extreme caution.Only if other drugs are not available and if clearly indicated. If treatment with life-sustaining drugs that cause pancreatic toxicity is required, suspension of didanosine is recommended [see Warnings and Precautions (5.1)].
Neurotoxic drugs	↑risk of neuropathy	Use with caution.[See Warnings and Precautions (5.5).]

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Table 4 Established and Potential Drug Interactions: Use With Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table 5 for Magnitude of Interaction.
* The interaction between immediate-release VIRAMUNE and the drug was evaluated in a clinical study. The results of drug interaction studies with immediate-release VIRAMUNE are expected to also apply to VIRAMUNE XR.
Drug Name	Effect on Concentration of Nevirapine or Concomitant Drug	Clinical Comment
HIV Antiviral Agents: Protease Inhibitors (PIs)
Atazanavir/Ritonavir*	↓ Atazanavir ↑ Nevirapine	Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.
Fosamprenavir*	↓Amprenavir ↑Nevirapine	Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended.
Fosamprenavir/Ritonavir*	↓Amprenavir ↑Nevirapine	No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.
Indinavir*	↓ Indinavir	The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.
Lopinavir/Ritonavir*	↓Lopinavir	Dosing in adult patients: A dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra^® prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.
Nelfinavir*	↓Nelfinavir M8 Metabolite ↓Nelfinavir C_min	The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.
Saquinavir/ritonavir	The interaction between nevirapine and saquinavir/ritonavir has not been evaluated	The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.
HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Efavirenz*	↓ Efavirenz	The appropriate doses of these combinations with respect to safety and efficacy have not been established.
Delavirdine Etravirine Rilpivirine	↓ Efavirenz	Plasma concentrations may be altered. Nevirapine should not be coadministered with another NNRTI as this combination has not been shown to be beneficial.
Other Agents
Analgesics: Methadone*	↓ Methadone	Methadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
Antiarrhythmics: Amiodarone, disopyramide, lidocaine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Antibiotics: Clarithromycin*	↓ Clarithromycin ↑ 14-OH clarithromycin	Clarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex , overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered.
Rifabutin*	↑Rifabutin	Rifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration.
Rifampin*	↓ Nevirapine	Nevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using a nevirapine-containing regimen may use rifabutin instead.
Anticonvulsants: Carbamazepine, clonazepam, ethosuximide	Plasma concentrations of nevirapine and the anticonvulsant may be decreased.	Use with caution and monitor virologic response and levels of anticonvulsants.
Antifungals: Fluconazole*	↑Nevirapine	Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.
Ketoconazole*	↓ Ketoconazole	Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug.
Itraconazole	↓ Itraconazole	Nevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.
Antithrombotics: Warfarin	Plasma concentrations may be decreased.	Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.
Calcium channel blockers: Diltiazem, nifedipine, verapamil	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Cancer chemotherapy: Cyclophosphamide	Plasma concentrations may be increased.	Appropriate doses for this combination have not been established.
Ergot alkaloids: Ergotamine	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus	Plasma concentrations may be decreased.	Appropriate doses for these combinations have not been established.
Motility agents: Cisapride	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Opiate agonists: Fentanyl	Plasma concentrations may be decreased.	Appropriate doses for this combination have not been established.
Oral contraceptives: Ethinyl estradiol and Norethindrone*	↓ Ethinyl estradiol ↓ Norethindrone	Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended.

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Table 3 Established and Other Potentially SignificantThis table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
Concomitant Drug Class: Drug Name	Effect	Clinical Comment
HIV antiviral agents
Protease inhibitor: atazanavir	↓atazanavir ↑ tenofovir	Coadministration of atazanavir with ATRIPLA is not recommended. Coadministration of atazanavir with either efavirenz or tenofovir DF decreases plasma concentrations of atazanavir. The combined effect of efavirenz plus tenofovir DF on atazanavir plasma concentrations is not known. Also, atazanavir has been shown to increase tenofovir concentrations. There are insufficient data to support dosing recommendations for atazanavir or atazanavir/ritonavir in combination with ATRIPLA.
Protease inhibitor: fosamprenavir calcium	↓ amprenavir	Fosamprenavir (unboosted): Appropriate doses of fosamprenavir and ATRIPLA with respect to safety and efficacy have not been established. Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when ATRIPLA is administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when ATRIPLA is administered with fosamprenavir plus ritonavir twice daily.
Protease inhibitor: indinavir	↓ indinavir	The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz.
Protease inhibitor: lopinavir/ritonavir	↓ lopinavir ↑ tenofovir	Do not use once daily administration of lopinavir/ritonavir. Dose increase of lopinavir/ritonavir is recommended for all patients when coadministered with efavirenz. Refer to the full prescribing information for lopinavir/ritonavir for guidance on coadministration with efavirenz- or tenofovir-containing regimens, such as ATRIPLA. Patients should be monitored for tenofovir-associated adverse reactions.
Protease inhibitor: ritonavir	↑ ritonavir ↑ efavirenz	When ritonavir 500 mg every 12 hours was coadministered with efavirenz 600 mg once daily, the combination was associated with a higher frequency of adverse clinical experiences (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Monitoring of liver enzymes is recommended when ATRIPLA is used in combination with ritonavir.
Protease inhibitor: saquinavir	↓ saquinavir	Appropriate doses of the combination of efavirenz and saquinavir/ritonavir with respect to safety and efficacy have not been established.
CCR5 co-receptor antagonist: maraviroc	↓ maraviroc	Efavirenz decreases plasma concentrations of maraviroc. Refer to the full prescribing information for maraviroc for guidance on coadministration with ATRIPLA.
NRTI: didanosine	↑ didanosine	Coadministration of ATRIPLA and didanosine should be undertaken with caution, and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions including pancreatitis, lactic acidosis, and neuropathy. A dose reduction of didanosine is recommended when coadministered with tenofovir DF. For additional information on coadministration with tenofovir DF-containing products, please refer to the didanosine prescribing information.
NNRTI: Other NNRTIs	↑ or ↓ efavirenz and/or NNRTI	Combining two NNRTIs has not been shown to be beneficial. ATRIPLA contains efavirenz and should not be coadministered with other NNRTIs.
Integrase strand transfer inhibitor: raltegravir	↓ raltegravir	Efavirenz reduces plasma concentrations of raltegravir. The clinical significance of this interaction has not been directly assessed.
Hepatitis C antiviral agents
Protease inhibitor: boceprevir	↓ boceprevir	Plasma trough concentrations of boceprevir were decreased when boceprevir was coadministered with efavirenz, which may result in loss of therapeutic effect. The combination should be avoided.
Protease inhibitor: simeprevir	↓ simeprevir ↔ efavirenz	Concomitant administration of simeprevir with efavirenz is not recommended because it may result in loss of therapeutic effect of simeprevir.
NS5A inhibitors/NS5B polymerase inhibitors: ledipasvir/sofosbuvir	↑ tenofovir	Patients receiving ATRIPLA and HARVONI^® (ledipasvir/sofosbuvir) concomitantly should be monitored for adverse reactions associated with tenofovir DF.
sofosbuvir/velpatasvir	↑ tenofovir ↓ velpatasvir	Coadministration of efavirenz-containing regimens and EPCLUSA^® (sofosbuvir/velpatasvir) is not recommended.
Other agents
Anticoagulant: warfarin	↑ or ↓ warfarin	Plasma concentrations and effects potentially increased or decreased by efavirenz.
Anticonvulsants: carbamazepine	↓ carbamazepine ↓ efavirenz	There are insufficient data to make a dose recommendation for ATRIPLA. Alternative anticonvulsant treatment should be used.
phenytoin phenobarbital	↓ anticonvulsant ↓ efavirenz	Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
Antidepressants: bupropion	↓ buproprion	The effect of efavirenz on bupropion exposure is thought to be due to the induction of bupropion metabolism. Increases in bupropion dosage should be guided by clinical response, but the maximum recommended dose of bupropion should not be exceeded.
sertraline	↓ sertraline	Increases in sertraline dose should be guided by clinical response.
Antifungals: itraconazole	↓ itraconazole ↓ hydroxy-itraconazole	Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.
ketoconazole	↓ ketoconazole	Drug interaction trials with ATRIPLA and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole.
posaconazole	↓ posaconazole	Avoid concomitant use unless the benefit outweighs the risks.
Anti-infective: clarithromycin	↓ clarithromycin ↑ 14-OH metabolite	Consider alternatives to macrolide antibiotics because of the risk of QT interval prolongation.
Antimycobacterial: rifabutin	↓ rifabutin	Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
rifampin	↓ efavirenz	If ATRIPLA is coadministered with rifampin to patients weighing 50 kg or more, an additional 200 mg/day of efavirenz is recommended.
Antimalarials: artemether/lumefantrine	↓ artemether ↓ dihydroartemisinin ↓ lumefantrine	Consider alternatives to artemether/lumefantrine because of the risk of QT interval prolongation.
atovaquone/proguanil	↓ atovaquone ↓ proguanil	Concomitant administration of atovaquone/proguanil with ATRIPLA is not recommended.
Calcium channel blockers: diltiazem	↓ diltiazem ↓ desacetyl diltiazem ↓ N-monodes-methyl diltiazem	Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of ATRIPLA is necessary when administered with diltiazem.
Others (e.g., felodipine, nicardipine, nifedipine, verapamil)	↓ calcium channel blocker	No data are available on the potential interactions of efavirenz with other calcium channel blockers that are substrates of CYP3A. The potential exists for reduction in plasma concentrations of the calcium channel blocker. Dose adjustments should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker).
HMG-CoA reductase inhibitors: atorvastatin pravastatin simvastatin	↓ atorvastatin ↓ pravastatin ↓ simvastatin	Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased with efavirenz. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
Hormonal contraceptives: Oral: ethinyl estradiol/norgestimate	↓ active metabolites of norgestimate	A reliable method of barrier contraception must be used in addition to hormonal contraceptives. Efavirenz had no effect on ethinyl estradiol concentrations, but progestin levels (norelgestromin and levonorgestrel) were markedly decreased. No effect of ethinyl estradiol/norgestimate on efavirenz plasma concentrations was observed.
Implant: etonogestrel	↓ etonogestrel	A reliable method of barrier contraception must be used in addition to hormonal contraceptives. The interaction between etonogestrel and efavirenz has not been studied. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.
Immunosuppressants: cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A	↓ immuno-suppressant	Decreased exposure of the immunosuppressant may be expected due to CYP3A induction by efavirenz. These immunosuppressants are not anticipated to affect exposure of efavirenz. Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with ATRIPLA.
Narcotic analgesic: methadone	↓ methadone	Coadministration of efavirenz in HIV-1 infected individuals with a history of injection drug use resulted in decreased plasma levels of methadone and signs of opiate withdrawal. Methadone dose was increased by a mean of 22% to alleviate withdrawal symptoms. Patients should be monitored for signs of withdrawal and their methadone dose increased as required to alleviate withdrawal symptoms.

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Table 2: Drug — Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion -the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine / Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥100 mg/day or equivalent); Octreotide (>100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport — but FT₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone > 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and / or TSH level alterations by various mechanisms.

Table name:

Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	Meperidine is contraindicated in patients who are receiving monoamine oxidase (MAOIs) or those who have recently received such agents. Therapeutic doses of meperidine have occasionally precipitated unpredictable, severe, and occasionally fatal reactions in patients who have received such agents within 14 days. The mechanism of these reactions is unclear, but may be related to a preexisting hyperphenylalaninemia. Some have been characterized by coma, severe respiratory depression, cyanosis, and hypotension, and have resembled the syndrome of acute narcotic overdose. Serotonin syndrome with agitation, hyperthermia, diarrhea, tachycardia, sweating, tremors and impaired consciousness may also occur. In other reactions the predominant manifestations have been hyperexcitability, convulsions, tachycardia, hyperpyrexia, and hypertension.
Intervention:	Do not use meperidine hydrochloride tablets in patients taking MAOIs or within 14 days of stopping such treatment. Intravenous hydrocortisone or prednisolone have been used to treat severe reactions, with the addition of intravenous chlorpromazine in those cases exhibiting hypertension and hyperpyrexia. The usefulness and safety of narcotic antagonists in the treatment of these reactions is unknown.)
Examples:	phenelzine, tranylcypromine, linezolid
Inhibitors of CYP3A4 and CYP2B6
Clinical Impact:	The concomitant use of meperidine hydrochloride tablets and CYP3A4 or CYP2B6 inhibitors can increase the plasma concentration of meperidine, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of meperidine hydrochloride tablets and CYP2B6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of meperidine hydrochloride tablets is achieved [see Warnings and Precautions (5.4)]. After stopping a CYP3A4 or CYP2B6 inhibitor, as the effects of the inhibitor decline, the meperidine plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to meperidine.
Intervention:	If concomitant use is necessary, consider dosage reduction of meperidine hydrochloride tablets until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. If a CYP3A4 or CYP2B6 inhibitor is discontinued, consider increasing the meperidine hydrochloride tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal.
Examples:	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 and CYP2B6 Inducers
Clinical Impact:	The concomitant use of meperidine hydrochloride tablets and CYP3A4 or CYP2B6 inducers can decrease the plasma concentration of meperidine [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to meperidine [see Warningsand Precautions (5.4)]. After stopping a CYP3A4 or CYP2B6 inducer, as the effects of the inducer decline, the meperidine plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.
Intervention:	If concomitant use is necessary, consider increasing the meperidine hydrochloride tablets dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. If a CYP3A4 or CYP2B6 inducer is discontinued, consider meperidine hydrochloride tablets dosage reduction and monitor for signs of respiratory depression.
Examples:	Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.5)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Warnings and Precautions 5.8].
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue meperidine hydrochloride tablets if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase inhibitors (MAOIs) (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue)
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of meperidine hydrochloride tablets and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Meperidine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of meperidine hydrochloride tablets and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when meperidine hydrochloride tablets is used concomitantly with anticholinergic drugs.
Acyclovir
Clinical Impact:	The concomitant use of acyclovir may increase the plasma concentrations of meperidine and its metabolite, normeperidine.
Intervention:	If concomitant use of acyclovir and meperidine hydrochloride tablets is necessary, monitor patients for respiratory depression and sedation at frequent intervals.
Cimetidine
Clinical Impact:	The concomitant use of cimetidine may reduce the clearance and volume of distribution of meperidine also the formation of the metabolite, normeperidine, in healthy subjects.
Intervention:	If concomitant use of cimetidine and meperidine hydrochloride tablets is necessary, monitor patients for respiratory depression and sedation at frequent intervals.

Table name:

Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
*Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	C _m _a _x
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing.
	20 mg/day	4 mg/day	1.6	-	Do not exceed 8 mg/day
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers)
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Table 7: Summary of AED Interactions with Oxcarbazepine
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400-2000	900	nc nc denotes a mean change of less than 10%	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100-150	600-1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250-500	600-1800 >1200-2400	nc Pediatrics up to 40% increase Mean increase in adults at high oxcarbazepine doses [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400-2800	600-1800	nc	18% decrease [CI: 13% decrease, 40% decrease]

Table name:

Interacting Drug	Interaction
Drugs known to prolong QT interval (e.g., Class IA and Class III antiarrhythmic agents).	Quinine sulfate prolongs QT interval, ECG abnormalities including QT prolongation and Torsades de Pointes. Avoid concomitant use (5.3).
Other antimalarials (e.g., halofantrine, mefloquine).	ECG abnormalities including QT prolongation Avoid concomitant use (5.3, 7.2).
CYP3A4 inducers or inhibitors	Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine (7.1).
CYP3A4 and CYP2D6 substrates	Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the co-administered drug (7.2).
Digoxin	Increased digoxin plasma concentration (5.8, 7.1).

Table name: Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. During concomitant use of naproxen and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of naproxen and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS: Renal Toxicity and Hyperkalemia ). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.

•
Drugs That Interfere with Hemostasis
Clinical Impact:
Intervention:	Monitor patients with concomitant use of naproxen with anticoagulants (e.g., warfarin-ephrine reuptake inhibitors (SNRIs)) for signs of bleeding (see WARNINGS: Hematologic Toxicity ).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS: Gastrointestinal Bleeding, Ulceration and Perforation ).
Intervention:	Concomitant use of naproxen and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS: Hematologic Toxicity ). Naproxen is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:
Intervention:
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention	During concomitant use of naproxen with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS: Renal Toxicity and Hyperkalemia ).
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of naproxen and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS: Gastrointestinal Bleeding, Ulceration and Perforation ).
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of naproxen and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen is not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxen is not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen and probenecid should be observed for adjustment of dose if required.
Other Albumin-Bound Drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ).
Intervention:	Patients simultaneously receiving naproxen and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

Table name:

Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily^*
Grapefruit juice	Avoid grapefruit juice

Table name:

Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2) ].
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate. [See Warnings and Precautions (5.9) .]
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.11) and Use in Specific Populations (8.5) ].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [See Adverse Reactions (6.1) .]
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions (5.16) ].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies in and postmarketing.
Sildenafil	Use with caution Two-fold increase in exposure	Monitor for sildenafil toxicity (see Clinical Pharmacology (12.3 )].
Duloxetine	Avoid Use Five-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx^®(didanosine) chewable/ buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2.4)] .	Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

Table name:

DRUG	DESCRIPTION OF INTERACTION
Heparin	Salicylate decreases platelet adhesiveness and interferes with hemostasis in heparintreated patients.
Pyrazinamide	Inhibits pyrazinamide induced hyperuricemia.
Uricosuric Agents	Effect of probenemide, sulfinpyrazone and phenylbutazone inhibited.

Table name:

Factors	Dosage Adjustments for Aripiprazole
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors	Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double usual dose over 1 to 2 weeks

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations

Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

Table name:

Table 8: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2) ]
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.6) ].
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5) ].
Oral antibiotic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs [see Adverse Reactions (6.1) ].
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anticoagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions (5.15) ].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution Two-fold increase in exposure	Monitor for sildenafil toxicity [see Clinical Pharmacology (12.3) ].
Duloxetine	Avoid Use Five-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity.
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of this product. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.12, 7.3)

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Inhibitors of CYP2D6
Clinical Impact:	The concomitant use of tramadol HCl and acetaminophen and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1, particularly when an inhibitor is added after a stable dose of tramadol HCl and acetaminophen is achieved. Since M1 is a more potent μ-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease and the M1 plasma concentration will increase which could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, and may cause potentially fatal respiratory depression [see Clinical Pharmacology (12.3)].
Intervention:	If concomitant use of a CYP2D6 inhibitor is necessary, follow patients closely for adverse reactions including opioid withdrawal, seizures and serotonin syndrome. If a CYP2D6 inhibitor is discontinued, consider lowering tramadol HCl and acetaminophen dosage until stable drug effects are achieved. Follow patients closely for adverse events including respiratory depression and sedation.
Examples	Quinidine, fluoxetine, paroxetine and bupropion
Inhibitors of CYP3A4
Clinical Impact:	The concomitant use of tramadol HCl and acetaminophen and CYP3A4 inhibitors can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1. Follow patients closely for increased risk of serious adverse events including seizures and serotonin syndrome, and adverse reactions related to opioid toxicity including potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of tramadol HCl and acetaminophen is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy and possibly signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol.
Intervention:	If concomitant use is necessary, consider dosage reduction of tramadol HCl and acetaminophen until stable drug effects are achieved. Follow patients closely for seizures and serotonin syndrome, and signs of respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the tramadol HCl and acetaminophen dosage until stable drug effects are achieved and follow patients for signs and symptoms of opioid withdrawal.
Examples	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact:	The concomitant use of tramadol HCl and acetaminophen and CYP3A4 inducers can decrease the plasma concentration of tramadol [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression, seizures and serotonin syndrome.
Intervention:	If concomitant use is necessary, consider increasing the tramadol HCl and acetaminophen dosage until stable drug effects are achieved. Follow patients for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider tramadol HCl and acetaminophen dosage reduction and monitor for seizures and serotonin syndrome, and signs of sedation and respiratory depression. Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of tramadol HCl and acetaminophen and carbamazepine is not recommended.
Examples:	Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.6)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue tramadol HCl and acetaminophen if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.7)] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
Intervention:	Do not use tramadol HCl and acetaminophen in patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of tramadol HCl and acetaminophen and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Tramadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of tramadol HCl and acetaminophen and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when tramadol HCl and acetaminophen is used concomitantly with anticholinergic drugs.
Digoxin
Clinical Impact:	Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity.
Intervention:	Follow patients for signs of digoxin toxicity and adjust dosage of digoxin as needed.
Warfarin
Clinical Impact:	Post-marketing surveillance of tramadol has revealed rare reports of alteration of warfarin effect, including elevation of prothrombin times.
Intervention:	Monitor the prothrombin time of patients on warfarin for signs of an interaction and adjust the dosage of warfarin as needed.

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Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.7)].
Benzodiazepines (e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.7)]	Monitor sedation and blood pressure. Adjust dose accordingly.

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Table 7: Summary of AED Interactions with Oxcarbazepine
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400 to 2000	900	ncnc denotes a mean change of less than 10%	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100 to 150	600 to 1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250 to 500	600 to 1800 >1200 to 2400	nc Pediatrics up to 40% increaseMean increase in adults at high oxcarbazepine doses [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400 to 2800	600 to 1800	nc	18% decrease [CI: 13% decrease, 40% decrease]

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Table 13 Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
↓ = Decreased (induces lamotrigine glucuronidation)
↑ = Increased (inhibits lamotrigine glucuronidation)
? = Conflicting data
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%
	? CBZ epoxide	May increase CBZ epoxide levels.
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold
	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9-Hydroxy- Risperidone) (Ratio*)		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	C_max
Enzyme (CYP2D6) Inhibitors			AUC	C_max
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed

Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparation containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine levels approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine (CBZ) and CBZ epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
	? CBZ epoxide	May increase CBZ epoxide levels
Phenobarbital/Primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin (PHT)	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
	? valproate	Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

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Factors	Dosage Adjustments for Aripiprazole Tablets
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
Known CYP2D6 Poor Metabolizers and strong CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors	Administer half of usual dose
Strong CYP2D6 and CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double usual dose over 1 to 2 weeks

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Factors	Dosage Adjustments for Aripiprazole
Known CYP2D6 Poor Metabolizers	Administer half of usual dose
Known CYP2D6 Poor Metabolizersand strong CYP3A4 inhibitors	Administer a quarter of usual dose
Strong CYP2D6 or CYP3A4 inhibitors	Administer half of usual dose
Strong CYP2D6 and CYP3A4inhibitors	Administer a quarter of usual dose
Strong CYP3A4 inducers	Double usual dose over 1 to 2 weeks

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AED Co - administered	AED Concentration	Topiramate Concentration
^a = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.
^b = Is not administered but is an active metabolite of carbamazepine.
NC = Less than 10% change in plasma concentration.
NE = Not Evaluated
Phenytoin	NC or 25% increase ^a	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide ^b	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Table 7 Summary of AED Interactions with Trileptal
AED Coadministered	Dose of AED (mg/day)	Trileptal Dose (mg/day)	Influence of Trileptal on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400-2000	900	nc¹	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100-150	600-1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250-500	600-1800 >1200-2400	nc^1,2 up to 40% increase³ [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400-2800	600-1800	nc¹	18% decrease [CI: 13% decrease, 40% decrease]

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Drugs that Affect Renal Function	A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDs], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics	Dofetilide	Concomitant administration with digoxin was associated with a higher rate of torsades de pointes.
	Sotalol	Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
	Dronedarone	Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog	Teriparatide	Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement	Thyroid	Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics	Epinephrine Norepinephrine Dopamine	Can increase the risk of cardiac arrhythmias.
Neuromuscular Blocking Agents	Succinylcholine	May cause sudden extrusion of potassium from muscle cells, causing arrhythmias in patients taking digoxin.
Supplements	Calcium	If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers		Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.

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Drugs that Affect Renal Function	A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDs], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics	Dofetilide	Concomitant administration with digoxin was associated with a higher rate of torsades de pointes.
	Sotalol	Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
	Dronedarone	Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog	Teriparatide	Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement	Thyroid	Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics	Epinephrine Norepinephrine Dopamine	Can increase the risk of cardiac arrhythmias.
Neuromuscular Blocking Agents	Succinylcholine	May cause sudden extrusion of potassium from muscle cells, causing arrhythmias in patients taking digoxin.
Supplements	Calcium	If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers		Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.
Ivabradine	Can increase the risk of bradycardia.

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Table III. Drugs That Have Been Documented Not to Interact With Theophylline or Drugs That Produce No Clinically Significant Interaction With TheophyllineRefer to PRECAUTIONS , Drug Interactions for information regarding table.
albuterol, systemic and inhaled amoxicillin ampicillin, with or without sulbactam atenolol azithromycin caffeine, dietary ingestion cefaclor co-trimoxazole (trimethoprim and sulfamethoxazole) diltiazem dirithromycin enflurane famotidine felodipine finasteride hydrocortisone isoflurane isoniazid isradipine influenza vaccine ketoconazole	lomefloxacin mebendazole medroxyprogesterone methylprednisolone metronidazole metoprolol nadolol nifedipine nizatidine norfloxacin ofloxacin omeprazole prednisone, prednisolone ranitidine rifabutin roxithromycin sorbitol (purgative doses do not inhibit theophylline absorption) sucralfate terbutaline, systemic terfenadine tetracycline tocainide

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Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of aripiprazole with strong CYP3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.7)].
Benzodiazepines(e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.7)].	Monitor sedation and blood pressure. Adjust dose accordingly.

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Interacting Drug	Interaction
Drugs known to prolong QT interval (e.g., Class IA and Class III antiarrhythmic agents).	Quinine sulfate capsules, USP prolongs QT interval, ECG abnormalities including QT prolongation and Torsades de Pointes. Avoid concomitant use (5.3).
Other antimalarials (e.g., halofantrine, mefloquine).	ECG abnormalities including QT prolongation. Avoid concomitant use (5.3, 7.2).
CYP3A4 inducers or inhibitors	Alteration in plasma quinine concentration. Monitor for lack of efficacy or increased adverse events of quinine (7.1).
CYP3A4 and CYP2D6 substrates	Quinine is an inhibitor of CYP3A4 and CYP2D6. Monitor for lack of efficacy or increased adverse events of the co-administered drug (7.2).
Digoxin	Increased digoxin plasma concentration (5.8, 7.1).

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Drugs That Interfere with Hemostasis
Clinical Impact:	• Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	• During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

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Table 6: Effect of VYVANSE on Other Drugs
Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Monoamine Oxidase Inhibitors (MAOIs)	Concomitant use of MAOIs and CNS stimulants can cause hypertensive crisis. Potential outcomes include death, stroke, myocardial infarction, aortic dissection, ophthalmological complications, eclampsia, pulmonary edema, and renal failure.	Do not administer VYVANSE concomitantly or within 14 days after discontinuing MAOI treatment [see Contraindications (4)]

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Table 5. Clinically-Significant Drug Interactions with Sertraline Hydrochloride
Monoamine Oxidase Inhibitors ( MAOIs )
Clinical Impact :	The concomitant use of SSRIs including sertraline hydrochloride and MAOIs increases the risk of serotonin syndrome.
Intervention :	Sertraline hydrochloride is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [ See Dosage and Administration ( 2 . 5 ), Contraindications ( 4 ), Warnings and Precautions ( 5 . 2)].
Examples :	selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
Pimozide
Clinical Impact :	Increased plasma concentrations of pimozide, a drug with a narrow therapeutic index, may increase the risk of QT prolongation and ventricular arrhythmias.
Intervention :	Concomitant use of pimozide and sertraline hydrochloride is contraindicated [ See Contraindications ( 4)].
Other Serotonergic Drugs
Clinical Impact :	The concomitant use of serotonergic drugs with sertraline hydrochloride increases the risk of serotonin syndrome.
Intervention :	Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of sertraline hydrochloride and/or concomitant serotonergic drugs [ See Warnings and Precautions ( 5 . 2)].
Examples :	other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John’s Wort
Drugs that Interfere with Hemostasis ( antiplatelet agents and anticoagulants )
Clinical Impact :	The concurrent use of an antiplatelet agent or anticoagulant with sertraline hydrochloride may potentiate the risk of bleeding.
Intervention :	Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline hydrochloride and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [ See Warnings and Precautions ( 5 . 3)].
Examples :	aspirin, clopidogrel, heparin, warfarin
Drugs Highly Bound to Plasma Protein
Clinical Impact :	Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of sertraline hydrochloride with another drug that is highly bound to plasma protein may increase free concentrations of sertraline hydrochloride or other tightly-bound drugs in plasma [ See Clinical Pharmacology ( 12 . 3 )].
Intervention :	Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-bound drugs as warranted.
Examples :	warfarin
Drugs Metabolized by CYP2D6
Clinical Impact :	Sertraline hydrochloride is a CYP2D6 inhibitor [ See Clinical Pharmacology ( 12 . 3)]. The concomitant use of sertraline hydrochloride with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate.
Intervention :	Decrease the dosage of a CYP2D6 substrate if needed with concomitant sertraline hydrochloride use. Conversely, an increase in dosage of a CYP2D6 substrate may be needed if sertraline hydrochloride is discontinued.
Examples :	propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol, nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine
Phenytoin
Clinical Impact :	Phenytoin is a narrow therapeutic index drug. Sertraline hydrochloride may increase phenytoin concentrations.
Intervention :	Monitor phenytoin levels when initiating or titrating sertraline hydrochloride. Reduce phenytoin dosage if needed.
Examples :	phenytoin, fosphenytoin

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidibetic agents	Carefully monitor blood glucose (5.12, 7.3)

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Table III. Drugs That Have Been Documented Not to Interact With Theophylline or Drugs That Produce No Clinically Significant Interaction With TheophyllineRefer to PRECAUTIONS , Drug Interactions for information regarding table.
albuterol, systemic and inhaled amoxicillin ampicillin, with or without sulbactam atenolol azithromycin caffeine, dietary ingestion cefaclor co-trimoxazole (trimethoprim and sulfamethoxazole) diltiazem dirithromycin enflurane famotidine felodipine finasteride hydrocortisone isoflurane isoniazid isradipine influenza vaccine ketoconazole	lomefloxacin mebendazole medroxyprogesterone methylprednisolone metronidazole metoprolol nadolol nifedipine nizatidine norfloxacin ofloxacin omeprazole prednisone, prednisolone ranitidine rifabutin roxithromycin sorbitol (purgative doses do not inhibit theophylline absorption) sucralfate terbutaline, systemic terfenadine tetracycline tocainide

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Concomitant Drug Class: Drug Name	Effect on Concentration of Amprenavir or Concomitant Drug	Clinical Comment
HIV-Antiviral Agents
Non-nucleoside reverse transcriptase inhibitor: Efavirenz^a	LEXIVA: ↓Amprenavir LEXIVA/ritonavir: ↓Amprenavir	Appropriate doses of the combinations with respect to safety and efficacy have not been established. An additional 100 mg/day (300 mg total) of ritonavir is recommended when efavirenz is administered with LEXIVA/ritonavir once daily. No change in the ritonavir dose is required when efavirenz is administered with LEXIVA plus ritonavir twice daily.
Non-nucleoside reverse transcriptase inhibitor: Nevirapine^a	LEXIVA: ↓Amprenavir ↑Nevirapine LEXIVA/ritonavir: ↓Amprenavir ↑Nevirapine	Coadministration of nevirapine and LEXIVA without ritonavir is not recommended. No dosage adjustment required when nevirapine is administered with LEXIVA/ritonavir twice daily. The combination of nevirapine administered with LEXIVA/ritonavir once-daily regimen has not been studied.
HIV protease inhibitor: Atazanavir^a	LEXIVA: Interaction has not been evaluated. LEXIVA/ritonavir: ↓Atazanavir ↔Amprenavir	Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitors: Indinavir^a, nelfinavir^a	LEXIVA: ↑Amprenavir Effect on indinavir and nelfinavir is not well established. LEXIVA/ritonavir: Interaction has not been evaluated.	Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitors: Lopinavir/ritonavir^a	↓Amprenavir ↓Lopinavir	An increased rate of adverse events has been observed. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitor: Saquinavir^a	LEXIVA: ↓Amprenavir Effect on saquinavir is not well established. LEXIVA/ritonavir: Interaction has not been evaluated.	Appropriate doses of the combination with respect to safety and efficacy have not been established.
Other Agents
Antiarrhythmics: Amiodarone, bepridil, lidocaine (systemic), and quinidine	↑Antiarrhythmics	Use with caution. Increased exposure may be associated with life-threatening reactions such as cardiac arrhythmias. Therapeutic concentration monitoring, if available, is recommended for antiarrhythmics.
Anticoagulant: Warfarin		Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: Carbamazepine, phenobarbital, phenytoin Phenytoin^a	LEXIVA: ↓Amprenavir LEXIVA/ritonavir: ↑Amprenavir ↓Phenytoin	Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations in patients taking these agents concomitantly. Plasma phenytoin concentrations should be monitored and phenytoin dose should be increased as appropriate. No change in LEXIVA/ritonavir dose is recommended.
Antidepressant: Paroxetine, trazodone	↓Paroxetine ↑Trazodone	Coadministration of paroxetine with LEXIVA/ritonavir significantly decreased plasma levels of paroxetine. Any paroxetine dose adjustment should be guided by clinical effect (tolerability and efficacy). Concomitant use of trazodone and LEXIVA with or without ritonavir may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as LEXIVA, the combination should be used with caution and a lower dose of trazodone should be considered.
Antifungals: Ketoconazole^a, itraconazole	↑Ketoconazole ↑Itraconazole	Increase monitoring for adverse events. LEXIVA: Dose reduction of ketoconazole or itraconazole may be needed for patients receiving more than 400 mg ketoconazole or itraconazole per day. LEXIVA/ritonavir: High doses of ketoconazole or itraconazole (>200 mg/day) are not recommended.
Antimycobacterial: Rifabutin^a	↑Rifabutin and rifabutin metabolite	A complete blood count should be performed weekly and as clinically indicated to monitor for neutropenia. LEXIVA: A dosage reduction of rifabutin by at least half the recommended dose is required. LEXIVA/ritonavir: Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (a maximum dose of 150 mg every other day or 3 times per week).
Benzodiazepines: Alprazolam, clorazepate, diazepam, flurazepam	↑Benzodiazepines	Clinical significance is unknown. A decrease in benzodiazepine dose may be needed.
Calcium channel blockers: Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine	↑Calcium channel blockers	Use with caution. Clinical monitoring of patients is recommended.
Corticosteroid: Dexamethasone	↓Amprenavir	Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations.
Histamine H₂-receptor antagonists: Cimetidine, famotidine, nizatidine, ranitidine^a	LEXIVA: ↓Amprenavir LEXIVA/ritonavir: Interaction not evaluated	Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations.
HMG-CoA reductase inhibitor: Atorvastatin^a, rosuvastatin	↑Atorvastatin ↑Rosuvastatin	Use the lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as fluvastatin or pravastatin.
Immunosuppressants: Cyclosporine, tacrolimus, rapamycin	↑Immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents.
Inhaled/nasal steroid: Fluticasone	LEXIVA: ↑Fluticasone LEXIVA/ritonavir: ↑Fluticasone	Use with caution. Consider alternatives to fluticasone, particularly for long-term use. May result in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushings syndrome and adrenal suppression have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone. Coadministration of fluticasone and LEXIVA/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
Narcotic analgesic: Methadone	↓Methadone	Data suggest that the interaction is not clinically relevant; however, patients should be monitored for opiate withdrawal symptoms.
Oral contraceptives: Ethinyl estradiol/norethin-drone^a	LEXIVA: ↓Amprenavir ↓Ethinyl estradiol LEXIVA/ritonavir: ↓Ethinyl estradiol	Alternative methods of non-hormonal contraception are recommended. May lead to loss of virologic response. ^* Increased risk of transaminase elevations. No data are available on the use of LEXIVA/ritonavir with other hormonal therapies, such as hormone replacement therapy (HRT) for postmenopausal women.
PDE5 inhibitors: Sildenafil, tadalafil, vardenafil	↑Sildenafil ↑Tadalafil ↑Vardenafil	May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, visual changes, and priapism. LEXIVA: Sildenafil: 25 mg every 48 hours. Tadalafil: no more than 10 mg every 72 hours. Vardenafil: no more than 2.5 mg every 24 hours. LEXIVA/ritonavir: Sildenafil: 25 mg every 48 hours. Tadalafil: no more than 10 mg every 72 hours. Vardenafil: no more than 2.5 mg every 72 hours.
Proton pump inhibitors: Esomeprazole^a, lansoprazole, omeprazole, pantoprazole, rabeprazole	LEXIVA: ↔Amprenavir ↑Esomeprazole LEXIVA/ritonavir: ↔Amprenavir ↔Esomeprazole	Proton pump inhibitors can be administered at the same time as a dose of LEXIVA with no change in plasma amprenavir concentrations.
Tricyclic antidepressants: Amitriptyline, imipramine	↑Tricyclics	Therapeutic concentration monitoring is recommended for tricyclic antidepressants.

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TABLE 1. Clinically Significant Drug Interactions with DILAUDID INJECTION and/or DILAUDID-HP INJECTION
Benzodiazepines and other Central Nervous System Depressants (CNS)
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines and other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.3)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue DILAUDID INJECTION and DILAUDID-HP INJECTION if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.3)]. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.
Intervention:	The use of DILAUDID INJECTION or DILAUDID-HP INJECTION is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of DILAUDID INJECTION and DILAUDID-HP INJECTION and/or precipitate withdrawal syndrome.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Hydromorphone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of DILAUDID INJECTION and DILAUDID-HP INJECTION and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when DILAUDID INJECTION and DILAUDID-HP INJECTION are used concomitantly with anticholinergic drugs.

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Drugs That Interfere with Hemostasis
Clinical Impact:	Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of naproxen sodium tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	Concomitant use of naproxen sodium tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen sodium tablets are not substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of naproxen sodium tablets and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of naproxen sodium tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention	During concomitant use of naproxen sodium tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of naproxen sodium tablets and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen sodium tablets and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen sodium tablets and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen sodium tablets and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen sodium tablets and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen sodium tablets with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen sodium tablets and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of naproxen sodium tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen sodium tablets are not recommended. Due to the gastric pH elevating effects of H ₂-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed-release tablets are not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxen sodium tablets is not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen sodium tablets and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:	Patients simultaneously receiving naproxen sodium tablets and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

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Table 14: Clinically Important Drug Interactions: Effect of other Drugs on Guanfacine Extended-Release Tablets
Concomitant Drug Name or Drug Class	Clinical Rationale and Magnitude of Drug Interaction	Clinical Recommendation
Strong and moderate CYP3A4 inhibitors, e.g., ketoconazole, fluconazole	Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in an increase in exposure	Consider dose reduction [see Dosage and administration (2.7) ]
Strong and moderate CYP3A4 inducers, e.g., rifampin, efavirenz	Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in a 60% decrease in exposure	Consider dose increase[see Dosage and administration (2.7) ]

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitors (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 4: Clinically Relevant Interactions Affecting Omeprazole When Co-Administered with Other Drugs
CYP2C19 or CYP3A4 Inducers
Clinical Impact:	Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention:	St. John’s Wort, rifampin: Avoid concomitant use with omeprazole [see Warnings and Precautions (5.9)]. Ritonavir-containing products: see prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:	Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
Intervention:	Voriconazole: Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dose adjustment may be considered. See prescribing information for voriconazole.

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Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)]
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.9)].
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.11) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs [see Adverse Reactions (6.1)].
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions (5.16)].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution Two-fold increase in exposure	Monitor for sildenafil toxicity [see Clinical Pharmacology (12.3)].
Duloxetine	Avoid Use Five-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx^® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2.4)].	Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid grapefruit juice

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Calcium Channel Blockers	Antifungals	Antibiotics	Glucocorticoids	Other Drugs
diltiazem	fluconazole	azithromycin	methylprednisolone	allopurinol
nicardipine	itraconazole	clarithromycin		amiodarone
verapamil	ketoconazole	erythromycin		bromocriptine
	voriconazole	quinupristin/dalfopristin		colchicine
				danazol
				imatinib
				metoclopramide
				nefazodone
				oral contraceptives

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Table 25: Clinically Important Drug Interactions with ABILIFY:
Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of ABILIFY with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of ABILIFY alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of ABILIFY with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the ABILIFY dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of ABILIFY and carbamazepine decreased the exposure of aripiprazole compared to the use of ABILIFY alone [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of ABILIFY with a strong CYP3A4 inducer, consider increasing the ABILIFY dosage [see DOSAGE AND ADMINISTRATION (2.7)].
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.7)].
Benzodiazepines (e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.7)]	Monitor sedation and blood pressure. Adjust dose accordingly.

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Table 3Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir )	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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^*For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily*
Grapefruit juice	Avoid grapefruit juice

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Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., ketoconazole) or strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine)	The concomitant use of oral aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole [see CLINICAL PHARMACOLOGY (12.3)].	With concomitant use of ABILIFY MAINTENA with a strong CYP3A4 inhibitor or CYP2D6 inhibitor for more than 14 days, reduce the ABILIFY MAINTENA dosage [see DOSAGE AND ADMINISTRATION (2.3)].
Strong CYP3A4 Inducers (e.g., carbamazepine)	The concomitant use of oral aripiprazole and carbamazepine decreased the exposure of aripiprazole [see CLINICAL PHARMACOLOGY (12.3)].	Avoid use of ABILIFY MAINTENA in combination with carbamazepine and other inducers of CYP3A4 for greater than 14 days [see DOSAGE AND ADMINISTRATION (2.3)].
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.7)].
Benzodiazepines (e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone [see WARNINGS AND PRECAUTIONS (5.7)].	Monitor sedation and blood pressure. Adjust dose accordingly.

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Inhibitors of CYP2D6
Clinical Impact:	The concomitant use of tramadol HCl and acetaminophen and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1, particularly when an inhibitor is added after a stable dose of tramadol HCl and acetaminophen is achieved. Since M1 is a more potent μ-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease and the M1 plasma concentration will increase which could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, and may cause potentially fatal respiratory depression [see Clinical Pharmacology (12.3)].
Intervention:	If concomitant use of a CYP2D6 inhibitor is necessary, follow patients closely for adverse reactions including opioid withdrawal, seizures and serotonin syndrome. If a CYP2D6 inhibitor is discontinued, consider lowering tramadol HCl and acetaminophen dosage until stable drug effects are achieved. Follow patients closely for adverse events including respiratory depression and sedation.
Examples	Quinidine, fluoxetine, paroxetine and bupropion
Inhibitors of CYP3A4
Clinical Impact:	The concomitant use of tramadol HCl and acetaminophen and CYP3A4 inhibitors can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1. Follow patients closely for increased risk of serious adverse events including seizures and serotonin syndrome, and adverse reactions related to opioid toxicity including potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of tramadol HCl and acetaminophen is achieved. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy and possibly signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol.
Intervention:	If concomitant use is necessary, consider dosage reduction of tramadol HCl and acetaminophen until stable drug effects are achieved. Follow patients closely for seizures and serotonin syndrome, and signs of respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the tramadol HCl and acetaminophen dosage until stable drug effects are achieved and follow patients for signs and symptoms of opioid withdrawal.
Examples	Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)
CYP3A4 Inducers
Clinical Impact:	The concomitant use of tramadol HCl and acetaminophen and CYP3A4 inducers can decrease the plasma concentration of tramadol [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase [see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression, seizures and serotonin syndrome.
Intervention:	If concomitant use is necessary, consider increasing the tramadol HCl and acetaminophen dosage until stable drug effects are achieved. Follow patients for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider tramadol HCl and acetaminophen dosage reduction and monitor for seizures and serotonin syndrome, and signs of sedation and respiratory depression. Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of tramadol HCl and acetaminophen and carbamazepine is not recommended.
Examples:	Rifampin, carbamazepine, phenytoin
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.6)].
Examples:	Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue tramadol HCl and acetaminophen if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome [see Warnings and Precautions (5.7)] or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2)].
Intervention:	Do not use tramadol HCl and acetaminophen in patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of tramadol HCl and acetaminophen and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Tramadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of tramadol HCl and acetaminophen and/or the muscle relaxant as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when tramadol HCl and acetaminophen is used concomitantly with anticholinergic drugs.
Digoxin
Clinical Impact:	Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity.
Intervention:	Follow patients for signs of digoxin toxicity and adjust dosage of digoxin as needed.
Warfarin
Clinical Impact:	Post-marketing surveillance of tramadol has revealed rare reports of alteration of warfarin effect, including elevation of prothrombin times.
Intervention:	Monitor the prothrombin time of patients on warfarin for signs of an interaction and adjust the dosage of warfarin as needed.

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Drugs That Interfere with Hemostasis
Clinical Impact:	• Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	• During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

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Drugs That Interfere with Hemostasis
Clinical Impact:	• Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	• During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

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Table 3: Clinically Significant drug interactions with Celecoxib
Drugs That Interfere with Hemostasis
Clinical Impact :	Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of Celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention :	Monitor patients with concomitant use of celecoxib capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions ( 5.11)].
Aspirin
Clinical Impact :	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions ( 5.2)]. In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200-400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100-325 mg).
Intervention :	Concomitant use of celecoxib capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions ( 5.11)]. Celecoxib capsules are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors , Angiotensin Receptor Blockers , and Beta - Blockers
Clinical Impact :	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention :	During concomitant use of celecoxib capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of celecoxib capsules and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions ( 5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact :	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention :	During concomitant use of celecoxib capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions ( 5.6)].
Digoxin
Clinical Impact :	The concomitant use of Celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention :	During concomitant use of celecoxib capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact :	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention :	During concomitant use of celecoxib capsules and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact :	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Celecoxib has no effect on methotrexate pharmacokinetics.
Intervention :	During concomitant use of celecoxib capsules and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact :	Concomitant use of celecoxib capsules and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention :	During concomitant use of celecoxib capsules and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact :	Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions ( 5.2)].
Intervention :	The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact :	Concomitant use of celecoxib capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention :	During concomitant use of celecoxib capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or inducers
Clinical Impact :	Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Coadministration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib.
Intervention :	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [see Clinical Pharmacology ( 12.3)].
CYP2D6 substrates
Clinical Impact :	In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs.
Intervention :	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [see Clinical Pharmacology ( 12.3)].
Corticosteroids
Clinical Impact :	Concomitant use of corticosteroids with celecoxib capsules may increase the risk of GI ulceration or bleeding.
Intervention :	Monitor patients with concomitant use of celecoxib capsules with corticosteroids for signs of bleeding [see Warnings and Precautions ( 5.2)].

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Table 3 Clinically Significant Drug Interactions with Meloxicam
Drugs that Interfere with Hemostasis
Clinical Impact :	Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention :	Monitor patients with concomitant use of meloxicam with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions ( 5 . 11)].
Aspirin
Clinical Impact :	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions ( 5 . 2)].
Intervention :	Concomitant use of meloxicam and low dose aspirin or analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions ( 5 . 11)]. Meloxicam is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors , Angiotensin Receptor Blockers , or Beta - Blockers
Clinical Impact :	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, coadministration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention :	During concomitant use of meloxicam and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of meloxicam and ACE inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions ( 5 . 6 )]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact :	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam.
Intervention :	During concomitant use of meloxicam with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see Warnings and Precautions ( 5 . 6)].
Lithium
Clinical Impact :	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis [ see Clinical Pharmacology ( 12 . 3)].
Intervention :	During concomitant use of meloxicam and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact :	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention :	During concomitant use of meloxicam and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact :	Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention :	During concomitant use of meloxicam and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact :	Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions ( 5 . 2)].
Intervention :	The concomitant use of meloxicam with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact :	Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention :	During concomitant use of meloxicam and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking meloxicam should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of meloxicam with pemetrexed is not recommended.

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Table 1: Drugs that may have their plasma concentrations increased by itraconazole
Drug Class	Contraindicated	Not Recommended	Use with Caution	Comments
	Under no circumstances is the drug to be coadministered with itraconazole, and up to two weeks after discontinuation of treatment with itraconazole.	It is recommended that the use of the drug be avoided during and up to two weeks after discontinuation of treatment with itraconazole, unless the benefits outweigh the potentially increased risks of side effects. If coadministration cannot be avoided, clinical monitoring for signs or symptoms of increased or prolonged effects or side effects of the interacting drug is recommended, and its dosage be reduced or interrupted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured. The label of the coadministered drug should be consulted for information on dose adjustment and adverse effects.	Careful monitoring is recommended when the drug is coadministered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely for signs or symptoms of increased or prolonged effects or side effects of the interacting drug, and its dosage be reduced as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured. The label of the coadministered drug should be consulted for information on dose adjustment and adverse effects.
Alpha Blockers		tamsulosin
Analgesics	methadone		alfentanil, buprenorphine IV and sublingual, fentanyl, oxycodone, sufentanil	Methadone: The potential increase in plasma concentrations of methadone when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation and torsade de pointes. Fentanyl: The potential increase in plasma concentrations of fentanyl when coadministered with itraconazole may increase the risk of potentially fatal respiratory depression. Sufentanil: No human pharmacokinetic data of an interaction with itraconazole are available. In vitro data suggest that sufentanil is metabolized by CYP3A4 and so potentially increased sufentanil plasma concentrations would be expected when coadministered with itraconazole.
Antiarrhythmics	disopyramide, dofetilide, dronedarone, quinidine		digoxin	Disopyramide, dofetilide, dronedarone, quinidine: The potential increase in plasma concentrations of these drugs when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation.
Antibacterials	telithromycin, in subjects with severe renal impairment or severe hepatic impairment	rifabutin	telithromycin	Telithromycin: The potential increase in plasma concentrations of telithromycin in subjects with severe renal impairment or severe hepatic impairment, when coadministered with itraconazole may increase the risk of serious cardiovascular events including QT prolongation and torsade de pointes. Rifabutin: See also under ‘Drugs that may decrease itraconazole plasma concentrations’.
Anticoagulants and Antiplatelet Drugs	ticagrelor	apixaban, rivaroxaban	coumarins, cilostazol, dabigatran	Ticagrelor: The potential increase in plasma concentrations of ticagrelor may increase the risk of bleeding. Coumarins: Itraconazole may enhance the anticoagulant effect of coumarin-like drugs, such as warfarin.
Anticonvulsants		carbamazepine		Carbamazepine: In vivo studies have demonstrated an increase in plasma carbamazepine concentrations in subjects concomitantly receiving ketoconazole. Although there are no data regarding the effect of itraconazole on carbamazepine metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of itraconazole and carbamazepine may inhibit the metabolism of carbamazepine. See also under ‘Drugs that may decrease itraconazole plasma concentrations’.
Antidiabetics			repaglinide, saxagliptin
Antihelmintics and Antiprotozoals			praziquantel
Antimigraine Drugs	ergot alkaloids, such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine)		eletriptan	Ergot Alkaloids: The potential increase in plasma concentrations of ergot alkaloids when coadministered with itraconazole may increase the risk of ergotism, i.e., a risk for vasospasm potentially leading to cerebral ischemia and/or ischemia of the extremities.
Antineoplastics	irinotecan	axitinib, dabrafenib, dasatinib, ibrutinib, nilotinib, sunitinib	bortezomib, busulphan, docetaxel, erlotinib, imatinib, ixabepilone, lapatinib, ponatinib, trimetrexate, vinca alkaloids	Irinotecan: The potential increase in plasma concentrations of irinotecan when coadministered with itraconazole may increase the risk of potentially fatal adverse events.
Antipsychotics, Anxiolytics and Hypnotics	lurasidone, oral midazolam, pimozide, triazolam		alprazolam, aripiprazole, buspirone, diazepam, haloperidol, midazolam IV, perospirone, quetiapine, ramelteon, risperidone	Midazolam, triazolam: Coadministration of itraconazole and oral midazolam, or triazolam may cause several-fold increases in plasma concentrations of these drugs. This may potentiate and prolong hypnotic and sedative effects, especially with repeated dosing or chronic administration of these agents. Pimozide: The potential increase in plasma concentrations of pimozide when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation and torsade de pointes.
Antivirals		simeprevir	maraviroc, indinavir, ritonavir, saquinavir	Indinavir, ritonavir: See also under ‘Drugs that may increase itraconazole plasma concentrations’.
Beta Blockers			nadolol
Calcium Channel Blockers	felodipine, nisoldipine		other dihydropyridines, verapamil	Calcium channel blockers canhave a negative inotropic effect which may be additive to those of itraconazole. The potential increase in plasma concentrations of calcium channel blockers when co-administered with itraconazole may increase the risk of congestive heart failure. Dihydropyridines: Concomitant administration of itraconazole may cause several-fold increases in plasma concentrations of dihydropyridines. Edema has been reported in patients concomitantly receiving itraconazole and dihydropyridine calcium channel blockers.
Cardiovascular Drugs, Miscellaneous	ranolazine	aliskiren, sildenafil, for the treatment of pulmonary hypertension	bosentan, riociguat	Ranolazine: The potential increase in plasma concentrations of ranolazine when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation.
Diuretics	eplerenone			Eplerenone: The potential increase in plasma concentrations of eplerenone when coadministered with itraconazole may increase the risk of hyperkalemia and hypotension.
Gastrointestinal Drugs	cisapride		aprepitant	Cisapride: The potential increase in plasma concentrations of cisapride when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation.
Immunosuppres sants		everolimus, temsirolimus	budesonide, ciclesonide, cyclosporine, dexamethasone, fluticasone, methylprednisolone, rapamycin (also known as sirolimus), tacrolimus
Lipid Regulating Drugs	lovastatin, simvastatin		atorvastatin	The potential increase in plasma concentrations of atorvastatin, lovastatin, and simvastatin when coadministered with itraconazole may increase the risk of skeletal muscle toxicity, including rhabdomyolysis.
Respiratory Drugs		salmeterol
Urological Drugs	fesoterodine, in subjects with moderate to severe renal impairment, or moderate to severe hepatic impairment, solifenacin, in subjects with severe renal impairment or moderate to severe hepatic impairment	darifenacin, vardenafil	fesoterodine. oxybutynin, sildenafil, for the treatment of erectile dysfunction, solifenacin, tadalafil, tolterodine	Fesoterodine: The potential increase in plasma concentrations of the fesoterodine active metabolite may be greater in subjects with moderate to severe renal impairment, or moderate to severe hepatic impairment, which may lead to an increased risk of adverse reactions. Solifenacin: The potential increase in plasma concentrations of solifenacin in subjects with severe renal impairment or moderate to severe hepatic impairment, when coadministered with itraconazole may increase the risk of serious cardiovascular events including QT prolongation.
Other	colchicine, in subjects with renal or hepatic impairment	colchicine, conivaptan, tolvaptan	cinacalcet	Colchicine: The potential increase in plasma concentrations of colchicine when coadministered with itraconazole may increase the risk of potentially fatal adverse events. Conivaptan and Tolvaptan: A safe and effective dose of either conivaptan or tolvaptan has not been established when coadministered with itraconazole.

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Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine concentrations approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine and carbamazepine epoxide	? carbamazepine epoxide	May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Drugs that Affect Renal Function	A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics	Dofetilide	Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
	Sotalol	Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
	Dronedarone	Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog	Teriparatide	Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement	Thyroid	Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics	Epinephrine Norepinephrine Dopamine	Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents	Succinylcholine	May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements	Calcium	If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers		Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis or with Grave’s disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T ₄ and T ₃levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine sodium should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin/Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens/Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non-Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT ₄ . Continued administration results in a decrease in serum T ₄ and normal FT ₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T ₄ and T ₃ to TBG and transthyretin. An initial increase in serum FT ₄ is followed by return of FT ₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T ₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T ₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ³ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T ₄ to T ₃, leading to decreased T ₃ levels. However, serum T ₄levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (>160 mg/day), T ₃ and T ₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T ₃concentrations by 30% with minimal change in serum T ₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T ₃ and T ₄levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³ I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily*
Grapefruit juice	Avoid grapefruit juice

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Table 1: Clinically Significant Drug Interactions with MS CONTIN
Benzodiazepines and Other Central Nervous System (CNS) Depressants
Clinical Impact:	Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation [see Warnings and Precautions (5.4)].
Examples:	Benzodiazepines and other sedative hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.
Serotonergic Drugs
Clinical Impact:	The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Intervention:	If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue MS CONTIN if serotonin syndrome is suspected.
Examples:	Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that effect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.6)].
Intervention:	Do not use MS CONTIN in patients taking MAOIs or within 14 days of stopping such treatment.
Examples:	phenelzine, tranylcypromine, linezolid
Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics
Clinical Impact:	May reduce the analgesic effect of MS CONTIN and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol, nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
Clinical Impact:	Morphine may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of MS CONTIN and/or the muscle relaxant as necessary.
Cimetidine
Clinical Impact:	The concomitant use of cimetidine can potentiate morphine effects and increase risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of MS CONTIN and/or cimetidine as necessary.
Diuretics
Clinical Impact:	Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.
Intervention:	Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when MS CONTIN is used concomitantly with anticholinergic drugs.
P-Glycoprotein (P-gp) Inhibitors
Clinical Impact:	The concomitant use of PGP-inhibitors can increase the exposure to morphine by about two-fold and can increase risk of hypotension, respiratory depression, profound sedation, coma, and death.
Intervention:	Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of MS CONTIN and/or the PGP-inhibitor as necessary.
Example:	Quinidine

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Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
*Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	Cmax
Enzyme (CYP2D6)inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not Needed

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blood dyscrasias -
see CONTRAINDICATIONS
cancer
collagen vascular disease
congestive heart failure

diarrhea
elevated temperature
hepatic disorders
infectious hepatitis
jaundice

hyperthyroidism
poor nutritional state
steatorrhea
vitamin K deficiency

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level ( 7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding ( 7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose ( 7)
Phenytoin	Monitor phenytoin level ( 7)
Methotrexate	Monitor for methotrexate toxicity ( 7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine ( 7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin ( 7)

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.3, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g.,Itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (>1 quart daily)

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Antibiotics	Anticonvulsants	Other Drugs/Dietary Supplements
nafcillin	carbamazepine	bosentan
rifampin	oxcarbazepine	octreotide
	phenobarbital	orlistat
	phenytoin	sulfinpyrazone
		St. John's Wort
		terbinafine
		ticlopidine

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Table 13. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation). ↑ = Increased (inhibits lamotrigine glucuronidation). ? = Conflicting data.
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( , , , ) 2.6 5.1 7 12.3
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Table 2 Steady-State Plasma Concentrations of Felbamate When Coadministered With Other AEDs
*Not administered but an active metabolite of carbamazepine.
**No significant effect.
AED Coadministered	AED Concentration	Felbamate Concentration
Phenytoin	↑	↓
Valproate	↑	↔**
Carbamazepine (CBZ) *CBZ epoxide	↓ ↑	↓
Phenobarbital	↑	↓

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Interacting DrugInteracting Drug	InteractionInteraction
Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.12, 7.3)

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Table 2. Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion – the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: Dopamine (≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide (> 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing radiographic contrast agents) Lithium Methimazole Propylthiouracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T₄ and T₃ serum transport - but FT₄ concentration remains normal; and therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide (> 80 mg IV) Heparin Hydantoins Non Steroidal Anti-Inflammatory Drugs - Fenamates - Phenylbutazone Salicylates (> 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄ is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T₄ and T₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased levothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free- T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T₄ 5'-deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids - (e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decreases the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol (> 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines. Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidinediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 2: Drugs That Affect Phenytoin Concentrations
* Antacids may affect absorption of phenytoin. † The induction potency of St. John's wort may vary widely based on preparation.
Interacting Agent	Examples
Drugs that may increase phenytoin serum levels
Antiepileptic drugs	Ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate
Azoles	Fluconazole, ketoconazole, itraconazole, miconazole, voriconazole
Antineoplastic agents	Capecitabine, fluorouracil
Antidepressants	Fluoxetine, fluvoxamine, sertraline
Gastric acid reducing agents	H₂ antagonists (cimetidine), omeprazole
Sulfonamides	Sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim
Other	Acute alcohol intake, amiodarone, chloramphenicol, chlordiazepoxide, disulfiram, estrogen, fluvastatin, isoniazid, methylphenidate, phenothiazines, salicylates, ticlopidine, tolbutamide, trazodone, warfarin
Drugs that may decrease phenytoin serum levels
Antacids*	Calcium carbonate, aluminum hydroxide, magnesium hydroxide Prevention or Management: Phenytoin and antacids should not be taken at the same time of day
Antineoplastic agents usually in combination	Bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate
Antiviral agents	Fosamprenavir, nelfinavir, ritonavir
Antiepileptic drugs	Carbamazepine, vigabatrin
Other	Chronic alcohol abuse, diazepam, diazoxide, folic acid, reserpine, rifampin, St. John's wort^†, sucralfate, theophylline
Drugs that may either increase or decrease phenytoin serum levels
Antiepileptic drugs	Phenobarbital, valproate sodium, valproic acid

Table name:

Interacting Agents	Prescribing Recommendations
Itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone	Avoid simvastatin
Gemfibrozil, cyclosporine, danazol	Do not exceed 10 mg simvastatin daily
Amiodarone, verapamil	Do not exceed 20 mg simvastatin daily
Grapefruit juice	Avoid large quantities of grapefruit juice (> 1 quart daily)

Table name:

Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine concentrations approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
Carbamazepine and carbamazepine epoxide	? carbamazepine epoxide	May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold.
Valproate	? valproate	There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

Table name:

Table 18Summary of Effect of Coadministered Drugs on Exposure to Active Moiety(Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients withSchizophrenia
*Change relative to reference
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9- Hydroxy- Risperidone (Ratio*)		Risperidone Dose Recommendation
	Coadministered Drug	Risperidone	AUC	C_m _a _x
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing.
	20 mg/day	4 mg/day	1.6	-	Do not exceed 8 mg/day
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/ PgP inducers)
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient’s usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

Table name:

Table 13. Established and Other Potentially Significant Drug Interactions
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
↓= Decreased (induces lamotrigine glucuronidation).
↑= Increased (inhibits lamotrigine glucuronidation).
? = Conflicting data.
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine	Decreased lamotrigine concentrations approximately 50%.
	↓ levonorgestrel	Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine	Addition of carbamazepine decreases lamotrigine concentration approximately 40%.
	? carbamazepine epoxide	May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine	Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.
Valproate	? valproate

Table name:

Table 3Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

Table name:

Drugs that Affect Renal Function	A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics	Dofetilide	Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
	Sotalol	Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
	Dronedarone	Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog	Teriparatide	Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement	Thyroid	Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics	Epinephrine Norepinephrine Dopamine	Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents	Succinylcholine	May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements	Calcium	If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers		Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.

Table name:

Table 2 Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

Table name:

Table 4 Established and Other Potentially SignificantThis table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class: Drug Name	Effect on ConcentrationIncrease=↑; Decrease=↓; No Effect=↔	Clinical Comment
Antacids: antacids (e.g., aluminium, magnesium hydroxide, or calcium carbonate)	↔ rilpivirine (antacids taken at least 2 hours before or at least 4 hours after rilpivirine) ↓ rilpivirine (concomitant intake)	The combination of COMPLERA and antacids should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). Antacids should only be administered either at least 2 hours before or at least 4 hours after COMPLERA.
Antimycobacterials: rifabutin	↓ rilpivirineThe interaction was evaluated in a clinical study. All other drug-drug interactions shown are predicted.	Concomitant use of COMPLERA with rifabutin may cause significant decreases in rilpivirine plasma concentrations (induction of CYP3A enzymes). If COMPLERA is coadministered with rifabutin, an additional 25 mg tablet of rilpivirine (Edurant) once per day is recommended to be taken concomitantly with COMPLERA and with a meal for the duration of rifabutin coadministration.
Azole Antifungal Agents: fluconazole itraconazole ketoconazole posaconazole voriconazole	↑ rilpivirine ^, This interaction study has been performed with a dose higher than the recommended dose for rilpivirine. The dosing recommendation is applicable to the recommended dose of rilpivirine 25 mg once daily. ↓ ketoconazole ^,	Concomitant use of COMPLERA with azole antifungal agents may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when COMPLERA is coadministered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are coadministered with COMPLERA.
Hepatitis C Antiviral Agents: ledipasvir/sofosbuvir sofosbuvir/velpatasvir	↑ tenofovir	Patients receiving COMPLERA concomitantly with HARVONI^®(ledipasvir/sofosbuvir) or EPCLUSA^® (sofosbuvir/velpatasvir) should be monitored for adverse reactions associated with tenofovir DF.
H₂-Receptor Antagonists: cimetidine famotidine nizatidine ranitidine	↔ rilpivirine ^, (famotidine taken 12 hours before rilpivirine or 4 hours after rilpivirine) ↓ rilpivirine ^, (famotidine taken 2 hours before rilpivirine)	The combination of COMPLERA and H₂-receptor antagonists should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). H₂-receptor antagonists should only be administered at least 12 hours before or at least 4 hours after COMPLERA.
Macrolide or Ketolide Antibiotics: clarithromycin erythromycin telithromycin	↑ rilpivirine ↔ clarithromycin ↔ erythromycin ↔ telithromycin	Concomitant use of COMPLERA with clarithromycin, erythromycin, or telithromycin may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Where possible, alternatives such as azithromycin should be considered.
Narcotic Analgesics: methadone	↓ R(–) methadone ↓ S(+) methadone ↔ rilpivirine ↔ methadone (when used with tenofovir)	No dose adjustments are required when initiating coadministration of methadone with COMPLERA. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients.

Table name:

Table 2: Drug-Thyroidal Axis Interactions
	Drug or Drug Class		Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
		Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
		Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
		Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
		Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
		Amiodarone Iodide (including iodine- containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
	Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
	Drugs that may increase		Drugs that may decrease
	serum TBG concentration		serum TBG concentration
	Clofibrate		Androgens / Anabolic Steroids
	Estrogen-containing oral		Asparaginase
	contraceptives		Glucocorticoids
	Estrogens (oral)		Slow-Release Nicotinic Acid
	Heroin / Methadone
	5-Fluorouracil
	Mitotane
	Tamoxifen
	Drugs that may cause protein-binding site displacement
	Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)		Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
	Carbamazepine Hydantoins Phenobarbital Rifampin		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
	Drugs that may decrease T ₄ 5' - deiodinase activity
	Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)		Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, Ieading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
	Miscellaneous
	Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives		Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
	Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
	Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin		Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
	Cardiac Glycosides		Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
	Cytokines - Interferon-α - Interleukin-2		Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
	Growth Hormones - Somatrem - Somatropin		Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
	Ketamine		Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
	Methylxanthine Bronchodilators - (e.g., Theophylline)		Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
	Radiographic Agents		Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
	Sympathomimetics		Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
	Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics		These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

Table name: Diclofenac and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of diclofenac and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.During concomitant use of diclofenac potassium tablets and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of diclofenac potassium tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS: Renal Toxicity and Hyperkalemia ). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.

Table 2. Clinically Significant Drug Interactions with Diclofenac
Drugs That Interfere with Hemostasis
Clinical Impact:
Intervention:	Monitor patients with concomitant use of diclofenac potassium tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS: Hematological Toxicity ).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ).
Intervention:	Concomitant use of diclofenac potassium tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS: Hematological Toxicity ). Diclofenac potassium tablets are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:
Intervention:
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of diclofenac potassium tablets with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS: Renal Toxicity and Hyperkalemia ).
Digoxin
Clinical Impact:	The concomitant use of diclofenac with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of diclofenac potassium tablets and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of diclofenac potassium tablets and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of diclofenac potassium tablets and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of diclofenac potassium tablets and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of diclofenac potassium tablets and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of diclofenac with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS: Gastrointestinal Bleeding, Ulceration, and Perforation ).
Intervention:	The concomitant use of diclofenac with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of diclofenac potassium tablets and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of diclofenac potassium tablets and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or Inducers:
Clinical Impact:	Diclofenac is metabolized by cytochrome P450 enzymes, predominantly by CYP2C9. Co-administration of diclofenac with CYP2C9 inhibitors (e.g. voriconazole) may enhance the exposure and toxicity of diclofenac whereas coadministration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of diclofenac.
Intervention:	A dosage adjustment may be warranted when diclofenac is administered with CYP2C9 inhibitors or inducers (see CLINICAL PHARMACOLOGY: Pharmacokinetics ).

Table name:

Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

Table name:

Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
StrongCYP3A4Inhibitors (e.g.,itraconazole,clarithromycin) or strongCYP2D6inhibitors (e.g.,quinidine,fluoxetine,paroxetine)	The concomitant use of aripiprazole tablets withstrong CYP3A4 orCYP2D6inhibitorsincreasedthe exposure ofaripiprazole tabletscomparedto the use of aripiprazole tabletsalone[seeCLINICALPHARMACOLOGY(12.3)].	Withconcomitant use of aripiprazole tablets with a strongCYP3A4inhibitororCYP2D6inhibitor, reducethearipiprazole tablets dosage[see DOSAGEANDADMINISTRATION(2.7)].
StrongCYP3A4Inducers (e.g.,carbamazepine,rifampin)	The concomitant use of aripiprazole tabletsandcarbamazepine decreased the exposure of aripiprazole tablets compared to the use of aripiprazole tablets alone [see CLINICALPHARMACOLOGY(12.3)].	Withconcomitant use of aripiprazole tablets with a strongCYP3A4inducer, consider increasing the aripiprazole tabletsdosage[see DOSAGE ANDADMINISTRATIO(2.7)].
AntihypertensiveDrugs	Duetoitsalphaadrenergicantagonism,aripiprazole tablets hasthepotentialtoenhance the effect of certainantihypertensive agents.	Monitor bloodpressureand adjustdoseaccordingly[seeWARNINGS AND PRECAUTIONS(5.7)].
Benzodiazepines(e.g., lorazepam)	Theintensityofsedationwas greaterwith the combination of oral aripiprazole tabletsandlorazepam as comparedtothat observedwith aripiprazole alone.Theorthostatichypotension observed wasgreaterwith the combination as comparedtothatobserved withlorazepamalone[seeWARNINGSANDPRECAUTIONS(5.7)]	Monitorsedation and blood pressure.Adjust dose accordingly.

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Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level. (5.9, 7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding. (7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose. (7)
Phenytoin	Monitor phenytoin level. (7)
Methotrexate	Monitor for methotrexate toxicity. (7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine. (7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin. (2.2, 7)

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Drugs that Affect Renal Function	A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics	Dofetilide	Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
	Sotalol	Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
	Dronedarone	Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog	Teriparatide	Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement	Thyroid	Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics	Epinephrine Norepinephrine Dopamine	Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents	Succinylcholine	May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements	Calcium	If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers		Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.

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Table 13. Established and Other Potentially Significant Drug Interactions
↓ = Decreased (induces lamotrigine glucuronidation). ↑ = Increased (inhibits lamotrigine glucuronidation). ? = Conflicting data.
Concomitant Drug	Effect on Concentration of Lamotrigine or Concomitant Drug	Clinical Comment
Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel	↓ lamotrigine ↓ levonorgestrel	Decreased lamotrigine concentrations approximately 50%. Decrease in levonorgestrel component by 19%.
Carbamazepine and carbamazepine epoxide	↓ lamotrigine ? carbamazepine epoxide	Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels.
Lopinavir/ritonavir	↓ lamotrigine	Decreased lamotrigine concentration approximately 50%.
Atazanavir/ritonavir	↓ lamotrigine	Decreased lamotrigine AUC approximately 32%.
Phenobarbital/primidone	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Phenytoin	↓ lamotrigine	Decreased lamotrigine concentration approximately 40%.
Rifampin	↓ lamotrigine	Decreased lamotrigine AUC approximately 40%.
Valproate	↑ lamotrigine ? valproate	Increased lamotrigine concentrations slightly more than 2-fold. There are conflicting study results regarding effect of lamotrigine on valproate concentrations: 1) a mean 25% decrease in valproate concentrations in healthy volunteers, 2) no change in valproate concentrations in controlled clinical trials in patients with epilepsy.

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Table 9. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug Name	Effect on Concentration of Lopinavir or Concomitant Drug	Clinical Comment
* see Clinical Pharmacology (12.3) for Magnitude of Interaction.
HIV-1 Antiviral Agents
Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz, nevirapine	↓ lopinavir	KALETRA dose increase is recommended in all patients [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)]. Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz. Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz. KALETRA should not be administered once daily in combination with efavirenz or nevirapine [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine	↑ lopinavir	Appropriate doses of the combination with respect to safety and efficacy have not been established.
Nucleoside Reverse Transcriptase Inhibitor: didanosine		KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).
Nucleoside Reverse Transcriptase Inhibitor: tenofovir	↑ tenofovir	KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitor: abacavir zidovudine	↓ abacavir ↓ zidovudine	KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.
HIV-1 Protease Inhibitor: amprenavir*	↑ amprenavir ↓ lopinavir	KALETRA should not be administered once daily in combination with amprenavir [see Dosage and Administration (2.1)].
HIV-1 Protease Inhibitor: fosamprenavir/ritonavir	↓ amprenavir ↓ lopinavir	An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: indinavir*	↑ indinavir	Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily [see Clinical Pharmacology (12.3)]. KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor: nelfinavir*	↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir	KALETRA should not be administered once daily in combination with nelfinavir [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].
HIV-1 Protease Inhibitor: ritonavir*	↑ lopinavir	Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: saquinavir*	↑ saquinavir	The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor: tipranavir	↓ lopinavir AUC and C_min	KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily).
HIV CCR5 – antagonist: maraviroc	↑ maraviroc	Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry^® (maraviroc).
Other Agents
Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), and quinidine	↑ antiarrhythmics	Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.
Anticancer Agents: vincristine, vinblastine, dasatinib, nilotinib	↑ anticancer agents	Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents. For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.
Anticoagulant: warfarin		Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: carbamazepine, phenobarbital, phenytoin	↓ lopinavir ↓ phenytoin	KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
Antidepressant: bupropion	↓ bupropion ↓ active metabolite, hydroxybupropion	Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant: trazodone	↑ trazodone	Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-infective: clarithromycin	↑ clarithromycin	For patients with renal impairment, the following dosage adjustments should be considered: For patients with CL_CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CL_CR < 30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary.
Antifungals: ketoconazole*, itraconazole, voriconazole	↑ ketoconazole ↑ itraconazole ↓ voriconazole	High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended. Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients.
Anti-gout: colchicine	↑ colchicine	Patients with renal or hepatic impairment should not be given colchicine with KALETRA. Treatment of gout flares-co-administration of colchicine in patients on KALETRA: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on KALETRA: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial: rifabutin*	↑ rifabutin and rifabutin metabolite	Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antimycobacterial: rifampin	↓ lopinavir	May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone [see Clinical Pharmacology (12.3) for magnitude of interaction].
Antiparasitic: atovaquone	↓ atovaquone	Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Benzodiazepines: parenterally administered midazolam	↑ midazolam	Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam [see Contraindications (4)]. If KALETRA is coadministered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Calcium Channel Blockers, dihydropyridine: e.g., felodipine, nifedipine, nicardipine	↑ dihydropyridine calcium channel blockers	Caution is warranted and clinical monitoring of patients is recommended.
Contraceptive: ethinyl estradiol*	↓ ethinyl estradiol	Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.
Corticosteroid: dexamethasone	↓ lopinavir	Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly.
disulfiram/metronidazole		KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Endothelin receptor antagonists: bosentan	↑ bosentan	Co-administration of bosentan in patients on KALETRA: In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Co-administration of KALETRA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA. After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin	↑ atorvastatin ↑ rosuvastatin	Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with KALETRA.
Immunosuppressants: cyclosporine, tacrolimus, rapamycin	↑ immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Inhaled Steroid: fluticasone	↑ fluticasone	Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect.
Long-acting beta-adrenoceptor agonist: salmeterol	↑ salmeterol	Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesic: methadone* fentanyl	↓ methadone ↑ fentanyl	Dosage of methadone may need to be increased when co-administered with KALETRA. Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA.
PDE5 inhibitors: sildenafil, tadalafil, vardenafil	↑ sildenafil ↑ tadalafil ↑ vardenafil	Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio^®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA [see Contraindications (4)]. The following dose adjustments are recommended for use of tadalafil (Adcirca^®) with KALETRA: Co-administration of ADCIRCA in patients on KALETRA: In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Co-administration of KALETRA in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: It is recommended not to exceed the following doses: Sildenafil: 25 mg every 48 hours Tadalafil: 10 mg every 72 hours Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events.

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class	Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate	Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration	Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen	Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)	Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin	Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)	Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives	Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)	Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin	Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides	Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2	Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin	Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine	Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)	Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents	Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics	Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics	These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Drugs that Affect Renal Function	A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics	Dofetilide	Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
	Sotalol	Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
	Dronedarone	Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog	Teriparatide	Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement	Thyroid Supplement	Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics	Epinephrine Norepinephrine Dopamine	Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents	Succinylcholine	May cause sudden extrusion of potassium from muscle cells causing arrhythmias inpatients taking digoxin.
Supplements	Calcium	If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers		Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.
Hyperpolarization-activated cyclic nucleotide-gated channel blocker	Ivabradine	Can increase the risk of bradycardia.

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Table 7 Summary of AED Interactions with Oxcarbazepine
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400-2000	900	nc¹	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100-150	600-1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250-500	600-1800 >1200-2400	nc^1,2 up to 40% increase³ [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400-2800	600-1800	nc¹	18% decrease [CI: 13% decrease, 40% decrease]

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Table 5: Effects on Steady-State Fexofenadine Pharmacokinetics After 7 Days of Coadministration With Fexofenadine Hydrochloride 120 mg Every 12 Hours in Healthy Adult Subjects (n = 24)
Concomitant Drug	C_maxSS (Peak plasma concentration)	AUC_ss(0-12h) (Extent of systemic exposure)
Erythromycin (500 mg every 8 hrs)	+82%	+109%
Ketoconazole (400 mg once daily)	+135%	+164%

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AED Co-administered	AED Concentration	Topiramate Concentration
NC = Less than 10% change in plasma concentration. NE = Not Evaluated
Phenytoin	NC or 25% increase = Plasma concentration increased 25% in some patients, generally those on a twice a day dosing regimen of phenytoin.	48% decrease
Carbamazepine (CBZ)	NC	40% decrease
CBZ epoxide = Is not administered but is an active metabolite of carbamazepine.	NC	NE
Valproic acid	11% decrease	14% decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NC at TPM doses up to 400 mg/day	13% decrease

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Table 6: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies [see Clinical Pharmacology (12.3) ( Tables 12 and 13) for magnitude of interaction]
Concomitant Drug Class: Drug Name	Effect on Concentration	Clinical Comment
HIV Antiviral Agents: Reverse Transcriptase Inhibitors
Delavirdine	↑ nelfinavir (C _min) ↓ delavirdine	Concentrations of nelfinavir were increased while concentrations of delavirdine were decreased when the two agents were coadministered. Appropriate doses of the combination, with respect to safety and efficacy, have not been established.
Nevirapine	↓ nelfinavir (C _min)	Concentrations of nelfinavir were decreased when coadministered with nevirapine. An appropriate dose of nelfinavir with respect to safety and efficacy has not been established.
Didanosine	↔ nelfinavir	There was no change in nelfinavir concentration when coadministered with didanosine. However, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after VIRACEPT (given with food).
HIV Antiviral Agents: Protease Inhibitors
Indinavir	↑ nelfinavir ↑ indinavir	Concentrations of both indinavir and nelfinavir were increased when the two agents were coadministered. Appropriate doses for these combinations, with respect to safety and efficacy, have not been established.
Ritonavir	↑ nelfinavir ↔ ritonavir	Concentrations of nelfinavir were increased when coadministered with ritonavir. An appropriate dose of nelfinavir for this combination, with respect to safety and efficacy, has not been established.
Saquinavir	↑ nelfinavir ↑ saquinavir	Concentrations of both saquinavir and nelfinavir were increased when the two agents were coadministered. Appropriate doses for these combinations, with respect to safety and efficacy, have not been established.
ANTICOAGULANT
Warfarin	Warfarin	Coadministration of warfarin and VIRACEPT may affect concentrations of warfarin. It is recommended that the INR (international normalized ratio) be monitored carefully during treatment with VIRACEPT, especially when commencing therapy.
ANTICONVULSANTS
Carbamazepine Phenobarbital Phenytoin	↓ nelfinavir ↓ phenytoin	Concentrations of nelfinavir may be decreased. VIRACEPT may not be effective due to decreased nelfinavir plasma concentrations in patients taking these agents concomitantly. Phenytoin plasma/serum concentrations should be monitored; phenytoin dose may require adjustment to compensate for altered phenytoin concentration.
ANTIDEPRESSANT
Trazodone	↑ trazodone	Concomitant use of trazodone and VIRACEPT may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as VIRACEPT, the combination should be used with caution and a lower dose of trazodone should be considered.
ANTIGOUT
Colchicine	↑ colchicines	Patients with renal or hepatic impairment should not be given colchicine with VIRACEPT due to the risk of colchicine toxicity. Treatment of gout flares – co- administration of colchicine in patients on VIRACEPT: 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout-flares – coadministration of colchicine in patients on VIRACEPT: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF)– coadministration of colchicine in patients on VIRACEPT: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
ANTIMYCOBACTERIAL
Rifabutin	↑ rifabutin ↓ nelfinavir (750 mg TID) ↔ nelfinavir (1250 mg BID)	It is recommended that the dose of rifabutin be reduced to one-half the usual dose when administered with VIRACEPT; 1250 mg BID is the preferred dose of VIRACEPT when coadministered with rifabutin.
ENDOTHELIN RECEPTOR ANTAGONIST
Bosentan	↑ bosentan	Concentrations of bosentan may be increased when coadministered with VIRACEPT. Coadministration of bosentan in patients on VIRACEPT or coadministration of VIRACEPT in patients on bosentan: Start at or adjust bosentan to 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA REDUCTASE INHIBITORS
Atorvastatin Rosuvastatin	↑ atorvastatin ↑ rosuvastatin	Titrate atorvastatin dose carefully and use the lowest necessary dose; do not exceed atorvastatin 40 mg/day.
IMMUNOSUPPRESSANTS
Cyclosporine Tacrolimus Sirolimus	↑ immuno-suppressants ↑ nelfinavir	Concentrations of these immunosuppressants and nelfinavir may be increased by coadministration of these agents with nelfinavir.
INHALED BETA AGONIST
Salmeterol	↑ salmeterol	Concurrent administration of salmeterol with VIRACEPT is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
INHALED/NASAL STEROID
Fluticasone	↑ fluticasone	Concomitant use of fluticasone propionate and VIRACEPT may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use.
MACROLIDE ANTIBIOTIC
Azithromycin	↑ azithromycin	Dose adjustment of azithromycin is not recommended, but close monitoring for known side effects such as liver enzyme abnormalities and hearing impairment is warranted.
NARCOTIC ANALGESIC
Methadone	↓ methadone	Concentrations of methadone were decreased when coadministered with VIRACEPT. Dosage of methadone may need to be increased when coadministered with VIRACEPT.
HORMONAL CONTRACEPTIVES
Ethinyl estradiol Norethindrone	↓ ethinyl estradiol ↓ norethindrone	Concentrations of ethinyl estradiol and norethindrone were decreased when coadministered with VIRACEPT. Alternative or additional contraceptive measures should be used when oral contraceptives containing ethinyl estradiol or norethindrone and VIRACEPT are coadministered.
PDE5 INHIBITORS
Sildenafil Vardenafil Tadalafil	↑ PDE5 Inhibitors	Concomitant use of PDE5 inhibitors and VIRACEPT should be undertaken with caution. May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): • Use of sildenafil (REVATIO) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications (4)] . • The following dose adjustments are recommended for use of tadalafil (ADCIRCA™) with VIRACEPT: Coadministration of ADCIRCA in patients on VIRACEPT or coadministration of VIRACEPT in patients on ADCIRCA: Start at or adjust ADCIRCA to 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: Sildenafil at a single dose not exceeding 25 mg in 48 hours, vardenafil at a single dose not exceeding 2.5 mg in 24 hours, or tadalafil at a single dose not exceeding 10 mg dose in 72 hours, is recommended. Use with increased monitoring for adverse events.
PROTON PUMP INHIBITORS
Omeprazole	↓ nelfinavir	Omeprazole decreases the plasma concentrations of nelfinavir. Concomitant use of proton pump inhibitors and VIRACEPT may lead to a loss of virologic response and development of resistance.
ANTIPSYCHOTICS
Quetiapine	↑ quetiapine	Initiation of VIRACEPT in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine drug exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking VIRACEPT: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.

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Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

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Classes of Drugs
Adrenal Cortical Steroid Inhibitors Antacids Antianxiety Agents Antiarrhythmics† Antibiotics† Anticonvulsants† Antidepressants† Antihistamines Antineoplastics†	Antipsychotic Medications Antithyroid Drugs† Barbiturates Diuretics† Enteral Nutritional Supplements Fungal Medications, Systemic† Gastric Acidity and Peptic Ulcer Agents† Hypnotics†	Hypolipidemics† Bile Acid-Binding Resins† HMG-CoA Reductase Inhibitors† Immunosuppressives Oral Contraceptives, Estrogen Containing Selective Estrogen Receptor Modulators Steroids, Adrenocortical† Tuberculosis Agents† Vitamins†

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Table 2: Drug-Thyroidal Axis Interactions
Drug or Drug Class			Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
Dopamine/Dopamine Agonists Glucocorticoids Octreotide			Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
Aminoglutethimide Amiodarone Iodide (including iodine-containing Radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide			Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
Amiodarone Iodide (including iodine-containing Radiographic contrast agents)			Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate			Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
Drugs that may increase serum TBG concentration			Drugs that may decrease serum TBG concentration
Clofibrate Estrogen-containing oral contraceptives Estrogens (oral) Heroin / Methadone 5-Fluorouracil Mitotane Tamoxifen			Androgens / Anabolic Steroids Asparaginase Glucocorticoids Slow-Release Nicotinic Acid
Drugs that may cause protein-binding site displacement
Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)			Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
Carbamazepine Hydantoins Phenobarbital Rifampin			Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
Drugs that may decrease T ₄ 5' - deiodinase activity
Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)			Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, leading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
Miscellaneous
Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives			Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)			Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin			Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
Cardiac Glycosides			Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
Cytokines - Interferon-α - Interleukin-2			Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
Growth Hormones - Somatrem - Somatropin			Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
Ketamine			Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
Methylxanthine Bronchodilators - (e.g., Theophylline)			Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
Radiographic Agents			Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
Sympathomimetics			Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics			These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Table 6. Effect of Other Drugs on Voriconazole Pharmacokinetics [see Clinical Pharmacology (12.3)]
Drug/Drug Class (Mechanism of Interaction by the Drug)	Voriconazole Plasma Exposure (C_max and AUCτ after 200 mg q12h)	Recommendations for Voriconazole Dosage Adjustment/Comments
Rifampin* and Rifabutin* (CYP450 Induction)	Significantly Reduced	Contraindicated
Efavirenz (400 mg q 24h) (CYP450 Induction) Efavirenz (300 mg q 24h) (CYP450 Induction)	Significantly Reduced Slight decrease in AUC_t	Contraindicated When voriconazole is coadministered with efavirenz, voriconazole oral maintenance dose should be increased to 400 mg q12h and efavirenz should be decreased to 300 mg q24h
High-dose Ritonavir (400 mg q12h)** (CYP450 Induction)	Significantly Reduced	Contraindicated
Low-dose Ritonavir (100 mg q12h)** (CYP450 Induction)	Reduced	Coadministration of voriconazole and low-dose ritonavir (100 mg q12h) should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole
Carbamazepine (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Long Acting Barbiturates (CYP450 Induction)	Not Studied In Vivo or In Vitro, but Likely to Result in Significant Reduction	Contraindicated
Phenytoin* (CYP450 Induction)	Significantly Reduced	Increase voriconazole maintenance dose from 4 mg/kg to 5 mg/kg IV q12h or from 200 mg to 400 mg orally q12h (100 mg to 200 mg orally q12h in patients weighing less than 40 kg)
St. John’s Wort (CYP450 inducer; P-gp inducer)	Significantly Reduced	Contraindicated
Oral Contraceptives** containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition)	Increased	Monitoring for adverse events and toxicity related to voriconazole is recommended when coadministered with oral contraceptives
Fluconazole** (CYP2C9, CYP2C19 and CYP3A4 Inhibition)	Significantly Increased	Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse events and toxicity related to voriconazole is started within 24 h after the last dose of fluconazole.
Other HIV Protease Inhibitors (CYP3A4 Inhibition)	In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism (Increased Plasma Exposure)	No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir Frequent monitoring for adverse events and toxicity related to voriconazole when coadministered with other HIV protease inhibitors
Other NNRTIs*** (CYP3A4 Inhibition or CYP450 Induction)	In Vitro Studies Demonstrated Potential for Inhibition of Voriconazole Metabolism by Delavirdine and Other NNRTIs (Increased Plasma Exposure)	Frequent monitoring for adverse events and toxicity related to voriconazole
	A Voriconazole-Efavirenz Drug Interaction Study Demonstrated the Potential for the Metabolism of Voriconazole to be Induced by Efavirenz and Other NNRTIs (Decreased Plasma Exposure)	Careful assessment of voriconazole effectiveness

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Interacting DrugInteracting Drug	InteractionInteraction
Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.12, 7.3)

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Table 3: Summary of AED Interactions with Oxcarbazepine
AED Coadministered	Dose of AED (mg/day)	Oxcarbazepine Dose (mg/day)	Influence of Oxcarbazepine on AED Concentration (Mean Change, 90% Confidence Interval)	Influence of AED on MHD Concentration (Mean Change, 90% Confidence Interval)
Carbamazepine	400 to 2000	900	nc¹	40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital	100 to 150	600 to 1800	14% increase [CI: 2% increase, 24% increase]	25% decrease [CI: 12% decrease, 51% decrease]
Phenytoin	250 to 500	600 to 1800 >1200 to 2400	nc^1,2 up to 40% increase³ [CI: 12% increase, 60% increase]	30% decrease [CI: 3% decrease, 48% decrease]
Valproic acid	400 to 2800	600 to 1800	nc¹	18% decrease [CI: 13% decrease, 40% decrease]

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NA - Not available/reported
Digoxin concentrations increased > 50%
	Digoxin Serum Concentration Increase	Digoxin AUC Increase	Recommendations
Amiodarone	70%	NA	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin dose by approximately 30% to 50% and continue monitoring.
Captopril	58%	39%
Nitrendipine	57%	15%
Propafenone	35-85%	NA
Quinidine	100%	NA
Ranolazine	87%	88%
Ritonavir	NA	86%
Verapamil	50-75%	NA
Digoxin concentrations increased < 50%
Carvedilol	16%	14%	Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin dose by approximately 15% to 30% and continue monitoring.
Diltiazem	20%	NA
Nifedipine	45%	NA
Rabeprazole	29%	19%
Telmisartan	20%	NA
Digoxin concentrations increased, but magnitude is unclear
Alprazolam, Azithromycin, Clarithromycin, Cyclosporine, Diclofenac, Diphenoxylate, Epoprostenol, Erythromycin, Esomeprazole, Indomethacin, Itraconazole, Ketoconazole, Lansoprazole, Metformin, Omeprazole, Propantheline, Spironolactone, Tetracycline			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
Digoxin concentrations decreased
Acarbose, Activated Charcoal, Albuterol, Antacids, Anticancer drugs, Cholestyramine, Colestipol, Exenatide, Kaolin-pectin, Meals High in Bran, Metoclpramide, Miglitol, Neomycin, Rifampin, Salbutamol, St.John's Wort, Sucralfate, Sulfasalazine			Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20% to 40% as necessary.
No significant Digoxin concentration changes
Please refer to section 12.3 for a complete list of drugs which were studied but reported no significant changes on digoxin exposure.			No additional actions are required.

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Table 2: Drug-Thyroidal Axis Interactions
	Drug or Drug Class		Effect
Drugs that may reduce TSH secretion - the reduction is not sustained; therefore, hypothyroidism does not occur
		Dopamine/Dopamine Agonists Glucocorticoids Octreotide	Use of these agents may result in a transient reduction in TSH secretion when administered at the following doses: dopamine ( ≥ 1 mcg/kg/min); Glucocorticoids (hydrocortisone ≥ 100 mg/day or equivalent); Octreotide ( > 100 mcg/day).
Drugs that alter thyroid hormone secretion
		Drugs that may decrease thyroid hormone secretion, which may result in hypothyroidism
		Aminoglutethimide Amiodarone Iodide (including iodine- containing radiographic contrast agents) Lithium Methimazole Propylthioracil (PTU) Sulfonamides Tolbutamide	Long-term lithium therapy can result in goiter in up to 50% of patients, and either subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonate, elderly and euthyroid patients with underlying thyroid disease (e.g., Hashimoto's thyroiditis or with Grave's disease previously treated with radioiodine or surgery) are among those individuals who are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are slowly excreted, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term amino-glu-tethimide therapy may minimally decrease T₄ and T₃ levels and increase TSH, although all values remain within normal limits in most patients.
		Drugs that may increase thyroid hormone secretion, which may result in hyperthyroidism
		Amiodarone Iodide (including iodine- containing Radiographic contrast agents)	Iodide and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave's disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyper functioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months after therapy discontinuation. Amiodarone may induce hyperthyroidism by causing thyroiditis.
Drugs that may decrease T ₄ absorption, which may result in hypothyroidism
	Antacids - Aluminum & Magnesium Hydroxides - Simethicone Bile Acid Sequestrants - Cholestyramine - Colestipol Calcium Carbonate Cation Exchange Resins - Kayexalate Ferrous Sulfate Orlistat Sucralfate		Concurrent use may reduce the efficacy of levothyroxine by binding and delaying or preventing absorption, potentially resulting in hypothyroidism. Calcium carbonate may form an insoluble chelate with levothyroxine, and ferrous sulfate likely forms a ferric-thyroxine complex. Administer levothyroxine at least 4 hours apart from these agents. Patients treated concomitantly with orlistat and levothyroxine should be monitored for changes in thyroid function.
Drugs that may alter T ₄ and T ₃ serum transport - but FT ₄ concentration remains normal; and, therefore, the patient remains euthyroid
	Drugs that may increase		Drugs that may decrease
	serum TBG concentration		serum TBG concentration
	Clofibrate		Androgens / Anabolic Steroids
	Estrogen-containing oral		Asparaginase
	contraceptives		Glucocorticoids
	Estrogens (oral)		Slow-Release Nicotinic Acid
	Heroin / Methadone
	5-Fluorouracil
	Mitotane
	Tamoxifen
	Drugs that may cause protein-binding site displacement
	Furosemide ( > 80 mg IV) Heparin Hydantoins Non Steroidal Anti-lnflammatory Drugs - Fenamates - Phenylbutazone Salicylates ( > 2 g/day)		Administration of these agents with levothyroxine results in an initial transient increase in FT₄. Continued administration results in a decrease in serum T₄ and normal FT₄ and TSH concentrations and, therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to TBG and transthyretin. An initial increase in serum FT₄, is followed by return of FT₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total-T₄ levels may decrease by as much as 30%.
Drugs that may alter T ₄ and T ₃ metabolism
Drugs that may increase hepatic metabolism, which may result in hypothyroidism
	Carbamazepine Hydantoins Phenobarbital Rifampin		Stimulation of hepatic microsomal drug-metabolizing enzyme activity may cause increased hepatic degradation of levothyroxine, resulting in increased Ievothyroxine requirements. Phenytoin and carbamazepine reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20% to 40%, but most patients have normal serum TSH levels and are clinically euthyroid.
	Drugs that may decrease T ₄ 5' - deiodinase activity
	Amiodarone Beta-adrenergic antagonists - (e.g., Propranolol > 160 mg/day) Glucocorticoids -(e.g., Dexamethasone ≥ 4 mg/day) Propylthiouracil (PTU)		Administration of these enzyme inhibitors decrease the peripheral conversion of T₄ to T₃, Ieading to decreased T₃ levels. However, serum T₄ levels are usually normal but may occasionally be slightly increased. In patients treated with large doses of propranolol ( > 160 mg/day), T₃ and T₄ levels change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular beta-adrenergic antagonists may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of glucocorticoids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term glucocorticoid therapy may result in slightly decreased T₃ and T₄ levels due to decreased TBG production (see above).
	Miscellaneous
	Anticoagulants (oral) - Coumarin Derivatives - Indandione Derivatives		Thyroid hormones appear to increase the catabolism of vitamin K-dependent clotting factors, thereby increasing the anticoagulant activity of oral anticoagulants. Concomitant use of these agents impairs the compensatory increases in clotting factor synthesis. Prothrombin time should be carefully monitored in patients taking levothyroxine and oral anticoagulants and the dose of anticoagulant therapy adjusted accordingly.
	Antidepressants - Tricyclics (e.g., Amitriptyline) - Tetracyclics (e.g., Maprotiline) - Selective Serotonin Reuptake Inhibitors (SSRIs; e.g., Sertraline)		Concurrent use of tri/tetracyclic antidepressants and levothyroxine may increase the therapeutic and toxic effects of both drugs, possibly due to increased receptor sensitivity to catecholamines.Toxic effects may include increased risk of cardiac arrhythmias and CNS stimulation; onset of action of tricyclics may be accelerated. Administration of sertraline in patients stabilized on levothyroxine may result in increased levothyroxine requirements.
	Antidiabetic Agents - Biguanides - Meglitinides - Sulfonylureas - Thiazolidediones - Insulin		Addition of levothyroxine to antidiabetic or insulin therapy may result in increased antidiabetic agent or insulin requirements. Careful monitoring of diabetic control is recommended, especially when thyroid therapy is started, changed, or discontinued.
	Cardiac Glycosides		Serum digitalis glycoside levels may be reduced in hyperthyroidism or when the hypothyroid patient is converted to the euthyroid state. Therapeutic effect of digitalis glycosides may be reduced.
	Cytokines - Interferon-α - Interleukin-2		Therapy with interferon-α has been associated with the development of antithyroid microsomal antibodies in 20% of patients and some have transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies before treatment are at higher risk for thyroid dysfunction during treatment. Interleukin-2 has been associated with transient painless thyroiditis in 20% of patients. Interferon-β and -γ have not been reported to cause thyroid dysfunction.
	Growth Hormones - Somatrem - Somatropin		Excessive use of thyroid hormones with growth hormones may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.
	Ketamine		Concurrent use may produce marked hypertension and tachycardia; cautious administration to patients receiving thyroid hormone therapy is recommended.
	Methylxanthine Bronchodilators - (e.g., Theophylline)		Decreased theophylline clearance may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.
	Radiographic Agents		Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.
	Sympathomimetics		Concurrent use may increase the effects of sympathomimetics or thyroid hormone. Thyroid hormones may increase the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease.
	Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine NITROPRUSSIDE Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics		These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

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Drugs That Interfere with Hemostasis
Clinical Impact:	• Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of Celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of celecoxib with anticoagulants (e.g., warfarin), antiplatelet agents(e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptakeinhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin doesnot produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitantuse of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactionsas compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. In two studies in healthy volunteers, and in patients with osteoarthritis and established heart diseaserespectively, celecoxib (200 to 400 mg daily) has demonstrated a lack of interference with the cardioprotectiveantiplatelet effect of aspirin (100 to 325 mg).
Intervention:	Concomitant use of celecoxib and analgesic doses of aspirin is not generally recommended because of theincreased risk of bleeding [see Warnings and Precautions (5.11)]. Celecoxib is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	• During concomitant use of celecoxib and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of celecoxib and ACE-inhibitors or ARBs in patients who are elderly, volume- depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect ofloop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to theNSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of celecoxib with diuretics, observe patients for signs of worsening renal function,in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions(5.6)].
Digoxin
Clinical Impact:	The concomitant use of Celecoxib with digoxin has been reported to increase the serum concentration andprolong the half-life of digoxin.
Intervention:	During concomitant use of celecoxib and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. Themean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of celecoxib and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g.,neutropenia, thrombocytopenia, renal dysfunction). Celecoxib has no effect on methotrexate pharmacokinetics.
Intervention:	During concomitant use of celecoxib and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of celecoxib and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of celecoxib and cyclosporine, monitor patients for signs of worsening renalfunction.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of Celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk ofGI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)].
Intervention:	The concomitant use of Celecoxib with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of celecoxib and pemetrexed may increase the risk of pemetrexed-associatedmyelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of celecoxib and pemetrexed, in patients with renal impairment whose creatinineclearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of twodays before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives(e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five daysbefore, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or inducers
Clinical Impact:	Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Coadministration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhancethe exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin)may lead to compromised efficacy of celecoxib.
Intervention:	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosageadjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers. [see Clinical Pharmacology (12.3)].
CYP2D6 substrates
Clinical Impact:	In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore,there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g.atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs.
Intervention:	Evaluate each patient’s medical history when consideration is given to prescribing celecoxib. A dosageadjustment may be warranted when celecoxib is administered with CYP2D6 substrates. [see Clinical Pharmacology (12.3)].
Corticosteroids
Clinical Impact:	Concomitant use of corticosteroids with celecoxib may increase the risk of GI ulceration or bleeding.
Intervention:	Monitor patients with concomitant use of celecoxib with corticosteroids for signs of bleeding [seeWarnings and Precautions (5.2)].

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Table 3: Drugs that Can Increase the Risk of Bleeding
Drug Class	Specific Drugs
Anticoagulants	argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin
Antiplatelet Agents	aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine
Nonsteroidal Anti-Inflammatory Agents	celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac
Serotonin Reuptake Inhibitors	citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Figure 6: Mean Standing Systolic Blood Pressure Change from Baseline

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Table II. Clinically significant drug interactions with theophylline.Refer to PRECAUTIONS, Drug Interactions for further information regarding table.
Drug	Type of Interaction	EffectAverage effect on steady-state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed.
Adenosine	Theophylline blocks adenosine receptors.	Higher doses of adenosine may be required to achieve desired effect.
Alcohol	A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours	30% increase
Allopurinol	Decreases theophylline clearance at allopurinol doses ≥ 600 mg/day	25% increase
Aminoglutethimide	Increases theophylline clearance by induction of microsomal enzyme activity.	25% decrease
Carbamazepine	Similar to aminoglutethimide.	30% decrease
Cimetidine	Decreases theophylline clearance by inhibiting cytochrome P450 1A2.	70% increase
Ciprofloxacin	Similar to cimetidine.	40% increase
Clarithromycin	Similar to erythromycin.	25% increase
Diazepam	Benzodiazepines increase CNS concentratrions of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors.	Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.
Disulfiram	Decreases theophylline clearance by inhibiting hydroxylation and demethylation.	50% increase
Enoxacin	Similar to cimetidine.	300% increase
Ephedrine	Synergistic CNS effects	Increased frequency of nausea, nervousness, and insomnia.
Erythromycin	Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3.	35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount.
Estrogen	Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance in unknown.	30% increase
Flurazepam	Similar to diazepam.	Similar to diazepam.
Fluvoxamine	Similar to cimetidine.	Similar to cimetidine.
Halothane	Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines.	Increased risk of ventricular arrhythmias.
Interferon, human recombinant alpha-A	Decreases theophylline clearance.	100% increase
Isoproterenol (IV)	Increase theophylline clearance.	20% increase
Ketamine	Pharmacologic	May lower theophylline seizure threshold.
Lithium	Theophylline increases renal lithium clearance.	Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%.
Lorazepam	Similar to diazepam.	Similar to diazepam.
Methotrexate (MTX)	Decreases theophylline clearance.	20% increase after low dose MTX, higher dose MTX may have a greater effect.
Mexiletine	Similar to disulfiram.	80% increase
Midazolam	Similar to diazepam.	Similar to diazepam.
Moricizine	Increases theophylline clearance.	25% increase
Pancuronium	Theophylline may antagonize non-depolarizing neuromuscular blocking effects;possibly due to phosphodiesterase inhibition.	Larger dose of pancuronium may be required to achieve neuromuscular blockade.
Pentoxifylline	Decreases theophylline clearance.	30% increase
Phenobarbital (PB)	Similar to aminoglutethimide.	25% decrease after two weeks of concurrent PB.
Phenytoin	Phenytoin increases theophylline clearance by increasing microsomal enzyme activity.	Serum theophylline and phenytoin concentrations decrease about 40%.
Propafenone	Decreases theophylline clearance and pharmacologic interaction.	40% increase. Beta-2 blocking effect may decrease efficacy of theophylline.
Propranolol	Similar to cimetidine and pharmacologic interaction.	100% increase Beta-2 blocking effect may decrease efficacy of theophylline.
Rifampin	Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity.	20-40% decrease
Sulfinpyrazone	Increase theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline.	20% increase
Tacrine	Similar to cimetidine, also increases renal clearance of theophylline.	90% increase
Thiabendazole	Decreases theophylline clearance.	190% increase
Ticlopidine	Decreases theophylline clearance.	60% increase
Troleandomycin	Similar to erythromycin.	33-100% increase depending on troleandomycin dose.
Verapamil	Similar to disulfiram.	20% increase

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Drugs That Interfere with Hemostasis
Clinical Impact:	• Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants has an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of naproxen or naproxen sodium with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding (see WARNINGS; Hematologic Toxicity).
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	Concomitant use of naproxen or naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding (see WARNINGS; Hematologic Toxicity). Naproxen or naproxen sodium is not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	• NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE-inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	• During concomitant use of naproxen or naproxen sodium and ACE inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen or naproxen sodium and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function (see WARNINGS; Renal Toxicity and Hyperkalemia). When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects (see WARNINGS; Renal Toxicity and Hyperkalemia).
Digoxin
Clinical Impact:	The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of naproxen or naproxen sodium and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of naproxen or naproxen sodium and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).
Intervention:	During concomitant use of naproxen or naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of naproxen or naproxen sodium and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy (see WARNINGS; Gastrointestinal Bleeding, Ulceration and Perforation).
Intervention:	The concomitant use of naproxen with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of naproxen or naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of naproxen or naproxen sodium and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
Antacids and Sucralfate
Clinical Impact:	Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen.
Intervention:	Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with naproxen or naproxen sodium is not recommended. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed release tablets are not recommended.
Cholestyramine
Clinical Impact:	Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention:	Concomitant administration of cholestyramine with naproxen or naproxen sodium is not recommended.
Probenecid
Clinical Impact:	Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and probenecid should be observed for adjustment of dose if required.
Other albumin-bound drugs
Clinical Impact:	Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin.
Intervention:	Patients simultaneously receiving naproxen or naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

Table name:

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.3, 2.4, 4, 5.1, 7.1, 7.2, 7.3, 12.3)
Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin daily For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

Table name:

Drugs That Interfere with Hemostasis
Clinical Impact:	Celecoxib and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of celecoxib and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone.
Intervention:	Monitor patients with concomitant use of celecoxib capsules with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [ see Warnings and Precautions (5.11) ].
Aspirin
Clinical Impact:	Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [ see Warnings and Precautions (5.2) ]. In two studies in healthy volunteers, and in patients with osteoarthritis and established heart disease respectively, celecoxib (200-400 mg daily) has demonstrated a lack of interference with the cardioprotective antiplatelet effect of aspirin (100-325 mg).
Intervention:	Concomitant use of celecoxib capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions (5.11) ]. Celecoxib capsules are not a substitute for low dose aspirin for cardiovascular protection.
ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers
Clinical Impact:	NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
Intervention:	During concomitant use of celecoxib capsules and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of celecoxib capsules and ACE-inhibitors or ARBs in patients who are elderly, volume- depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions (5.6) ]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter.
Diuretics
Clinical Impact:	Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of celecoxib capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see Warnings and Precautions (5.6) ].
Digoxin
Clinical Impact:	The concomitant use of celecoxib with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
Intervention:	During concomitant use of celecoxib capsules and digoxin, monitor serum digoxin levels.
Lithium
Clinical Impact:	NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis.
Intervention:	During concomitant use of celecoxib capsules and lithium, monitor patients for signs of lithium toxicity.
Methotrexate
Clinical Impact:	Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Celecoxib capsules have no effect on methotrexate pharmacokinetics.
Intervention:	During concomitant use of celecoxib capsules and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine
Clinical Impact:	Concomitant use of celecoxib capsules and cyclosporine may increase cyclosporine’s nephrotoxicity.
Intervention:	During concomitant use of celecoxib capsules and cyclosporine, monitor patients for signs of worsening renal function.
NSAIDs and Salicylates
Clinical Impact:	Concomitant use of celecoxib with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions (5.2) ].
Intervention:	The concomitant use of celecoxib with other NSAIDs or salicylates is not recommended.
Pemetrexed
Clinical Impact:	Concomitant use of celecoxib capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).
Intervention:	During concomitant use of celecoxib capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration.
CYP2C9 Inhibitors or inducers
Clinical Impact:	Celecoxib metabolism is predominantly mediated via cytochrome P450 (CYP) 2C9 in the liver. Co-administration of celecoxib with drugs that are known to inhibit CYP2C9 (e.g. fluconazole) may enhance the exposure and toxicity of celecoxib whereas co-administration with CYP2C9 inducers (e.g. rifampin) may lead to compromised efficacy of celecoxib.
Intervention	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2C9 inhibitors or inducers [ see Clinical Pharmacology (12.3) ].
CYP2D6 substrates
Clinical Impact:	In vitro studies indicate that celecoxib, although not a substrate, is an inhibitor of CYP2D6. Therefore, there is a potential for an in vivo drug interaction with drugs that are metabolized by CYP2D6 (e.g. atomoxetine), and celecoxib may enhance the exposure and toxicity of these drugs.
Intervention	Evaluate each patient's medical history when consideration is given to prescribing celecoxib. A dosage adjustment may be warranted when celecoxib is administered with CYP2D6 substrates [ see Clinical Pharmacology (12.3) ].
Corticosteroids
Clinical Impact:	Concomitant use of corticosteroids with celecoxib capsules may increase the risk of GI ulceration or bleeding.
Intervention	Monitor patients with concomitant use of celecoxib capsules with corticosteroids for signs of bleeding [see Warnings and Precautions (5.2)].

Table name:

Interacting Agents	Prescribing Recommendations
Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol	Contraindicated with simvastatin
Verapamil, diltiazem, dronedarone	Do not exceed 10 mg simvastatin daily
Amiodarone, amlodipine, ranolazine	Do not exceed 20 mg simvastatin daily
Lomitapide	For patients with HoFH, do not exceed 20 mg simvastatin dailyFor patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide.
Grapefruit juice	Avoid grapefruit juice

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Table 8: Clinically Significant Drug Interactions with Clarithromycin
Drugs That Are Affected By Clarithromycin
Drug(s) with Pharmacokinetics Affected by Clarithromycin	Recommendation	Comments
Antiarrhythmics:
Disopyramide Quinidine Dofetilide Amiodarone Sotalol Procainamide	Not Recommended	Disopyramide, Quinidine: There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide. Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs [see Warnings and Precautions (5.3)] . Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine. There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore, blood glucose levels should be monitored during concomitant administration of clarithromycin and disopyramide.
Digoxin	Use With Caution	Digoxin: Digoxin is a substrate for P-glycoprotein (Pgp) and clarithromycin is known to inhibit Pgp. When clarithromycin and digoxin are co-administered, inhibition of Pgp by clarithromycin may lead to increased exposure of digoxin. Elevated digoxin serum concentrations in patients receiving clarithromycin and digoxin concomitantly have been reported in postmarketing surveillance. Some patients have shown clinical signs consistent with digoxin toxicity, including potentially fatal arrhythmias. Monitoring of serum digoxin concentrations should be considered, especially for patients with digoxin concentrations in the upper therapeutic range.
Oral Anticoagulants:
Warfarin	Use With Caution	Oral anticoagulants: Spontaneous reports in the postmarketing period suggest that concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving clarithromycin and oral anticoagulants simultaneously [see Warnings and Precautions (5.4)] .
Antiepileptics:
Carbamazepine	Use With Caution	Carbamazepine: Concomitant administration of single doses of clarithromycin and carbamazepine has been shown to result in increased plasma concentrations of carbamazepine. Blood level monitoring of carbamazepine may be considered. Increased serum concentrations of carbamazepine were observed in clinical trials with clarithromycin. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with carbamazepine.
Antifungals:
Itraconazole	Use With Caution	Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly (see also Itraconazole under “Drugs That Affect Clarithromycin” in the table below). Clarithromycin may increase the plasma concentrations of itraconazole. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions.
Fluconazole	No Dose Adjustment	Fluconazole: [see Pharmacokinetics (12.3)]
Anti-Gout Agents:
Colchicine (in patients with renal or hepatic impairment)	Contraindicated	Colchicine: Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp). Clarithromycin and other macrolides are known to inhibit CYP3A and Pgp. The dose of colchicine should be reduced when co-administered with clarithromycin in patients with normal renal and hepatic function [see Contraindications (4.4) and Warnings and Precautions (5.4)] .
Colchicine (in patients with normal renal and hepatic function)	Use With Caution
Antipsychotics:
Pimozide	Contraindicated	Pimozide: [See Contraindications (4.2)]
Quetiapine		Quetiapine: Quetiapine is a substrate for CYP3A4, which is inhibited by clarithromycin. Co-administration with clarithromycin could result in increased quetiapine exposure and possible quetiapine related toxicities. There have been postmarketing reports of somnolence, orthostatic hypotension, altered state of consciousness, neuroleptic malignant syndrome, and QT prolongation during concomitant administration. Refer to quetiapine prescribing information for recommendations on dose reduction if co-administered with CYP3A4 inhibitors such as clarithromycin.
Antispasmodics:
Tolterodine (patients deficient in CYP2D6 activity)	Use With Caution	Tolterodine: The primary route of metabolism for tolterodine is via CYP2D6. However, in a subset of the population devoid of CYP2D6, the identified pathway of metabolism is via CYP3A. In this population subset, inhibition of CYP3A results in significantly higher serum concentrations of tolterodine. Tolterodine 1 mg twice daily is recommended in patients deficient in CYP2D6 activity (poor metabolizers) when co-administered with clarithromycin.
Antivirals:
Atazanavir	Use With Caution	Atazanavir: Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)] .
Saquinavir (in patients with decreased renal function)		Saquinavir: Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction (see Saquinavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)] .
Ritonavir Etravirine		Ritonavir, Etravirine: (see Ritonavir and Etravirine under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3)] .
Maraviroc		Maraviroc: Clarithromycin may result in increases in maraviroc exposures by inhibition of CYP3A metabolism. See Selzentry ^® prescribing information for dose recommendation when given with strong CYP3A inhibitors such as clarithromycin.
Boceprevir (in patients with normal renal function) Didanosine	No Dose Adjustment	Boceprevir: Both clarithromycin and boceprevir are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when co-administered. No dose adjustments are necessary for patients with normal renal function (see Victrelis ^® prescribing information).
Zidovudine		Zidovudine: Simultaneous oral administration of clarithromycin immediate-release tablets and zidovudine to HIV-infected adult patients may result in decreased steady-state zidovudine concentrations. Administration of clarithromycin and zidovudine should be separated by at least two hours [see Pharmacokinetics (12.3)] . The impact of co-administration of clarithromycin extended-release tablets or granules and zidovudine has not been evaluated.
Calcium Channel Blockers:
Verapamil	Use With Caution	Verapamil: Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, [see Warnings and Precautions (5.4)] .
Amlodipine Diltiazem		Amlodipine, Diltiazem: [See Warnings and Precautions (5.4)]
Nifedipine		Nifedipine: Nifedipine is a substrate for CYP3A. Clarithromycin and other macrolides are known to inhibit CYP3A. There is potential of CYP3A-mediated interaction between nifedipine and clarithromycin. Hypotension and peripheral edema were observed when clarithromycin was taken concomitantly with nifedipine [see Warnings and Precautions (5.4)] .
Ergot Alkaloids:
Ergotamine Dihydroergotamine	Contraindicated	Ergotamine, Dihydroergotamine: Postmarketing reports indicate that coadministration of clarithromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system [see Contraindications (4.6)] .
Gastroprokinetic Agents:
Cisapride	Contraindicated	Cisapride: [See Contraindications (4.2)]
HMG-CoA Reductase Inhibitors:
Lovastatin Simvastatin	Contraindicated	Lovastatin, Simvastatin, Atorvastatin, Pravastatin, Fluvastatin: [See Contraindications (4.5) and Warnings and Precautions (5.4)]
Atorvastatin Pravastatin	Use With Caution
Fluvastatin	No Dose Adjustment
Hypoglycemic Agents:
Nateglinide Pioglitazone Repaglinide Rosiglitazone	Use With Caution	Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]
Insulin		Insulin: [See Warnings and Precautions (5.4) and Adverse Reactions (6.2)]
Immunosuppressants:
Cyclosporine	Use With Caution	Cyclosporine: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine.
Tacrolimus		Tacrolimus: There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with tacrolimus.
Phosphodiesterase inhibitors:
Sildenafil Tadalafil Vardenafil	Use With Caution	Sildenafil, Tadalafil, Vardenafil: Each of these phosphodiesterase inhibitors is primarily metabolized by CYP3A, and CYP3A will be inhibited by concomitant administration of clarithromycin. Co-administration of clarithromycin with sildenafil, tadalafil, or vardenafil will result in increased exposure of these phosphodiesterase inhibitors. Co-administration of these phosphodiesterase inhibitors with clarithromycin is not recommended. Increased systemic exposure of these drugs may occur with clarithromycin; reduction of dosage for phosphodiesterase inhibitors should be considered (see their respective prescribing information).
Proton Pump Inhibitors:
Omeprazole	No Dose Adjustment	Omeprazole: The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when coadministered with clarithromycin as a result of increased omeprazole exposures [see Pharmacokinetics (12.3)] (see also Omeprazole under “Drugs That Affect Clarithromycin” in the table below).
Xanthine Derivatives:
Theophylline	Use With Caution	Theophylline: Clarithromycin use in patients who are receiving theophylline may be associated with an increase of serum theophylline concentrations [see Pharmacokinetics (12.3)] . Monitoring of serum theophylline concentrations should be considered for patients receiving high doses of theophylline or with baseline concentrations in the upper therapeutic range.
Triazolobenzodiazepines and Other Related Benzodiazepines:
Midazolam	Use With Caution	Midazolam: When oral midazolam is co-administered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated [see Warnings and Precautions (5.4) and Pharmacokinetics (12.3)] .
Alprazolam Triazolam		Triazolam, Alprazolam: Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is co-administered with clarithromycin. There have been postmarketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested. In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines.
Temazepam Nitrazepam Lorazepam	No Dose Adjustment	Temazepam, Nitrazepam, Lorazepam: For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.
Cytochrome P450 Inducers:
Rifabutin	Use With Caution	Rifabutin: Concomitant administration of rifabutin and clarithromycin resulted in an increase in rifabutin, and decrease in clarithromycin serum levels together with an increased risk of uveitis (see Rifabutin under “Drugs That Affect Clarithromycin” in the table below).
Other Drugs Metabolized by CYP3A:
Alfentanil Bromocriptine Cilostazol Methylprednisole Vinblastine Phenobarbital St. John’s Wort	Use With Caution	There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St. John’s Wort.
Other Drugs Metabolized by CYP450 Isoforms Other than CYP3A:
Hexobarbital Phenytoin Valproate	Use With Caution	There have been postmarketing reports of interactions of clarithromycin with drugs not thought to be metabolized by CYP3A, including hexobarbital, phenytoin, and valproate.
Drugs that Affect Clarithromycin
Drug(s) that Affect the Pharmacokinetics of Clarithromycin	Recommendation	Comments
Antifungals:
Itraconazole	Use With Caution	Itraconazole: Itraconazole may increase the plasma concentrations of clarithromycin. Patients taking itraconazole and clarithromycin concomitantly should be monitored closely for signs or symptoms of increased or prolonged adverse reactions (see also Itraconazole under “Drugs That Are Affected By Clarithromycin” in the table above).
Antivirals:
Atazanavir	Use With Caution	Atazanavir: When clarithromycin is co-administered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology (12.3)] . Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex. Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.
Ritonavir (in patients with decreased renal function)		Ritonavir: Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with ritonavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium [see Pharmacokinetics (12.3)] . Doses of clarithromycin greater than 1000 mg per day should not be co-administered with protease inhibitors.
Saquinavir (in patients with decreased renal function)		Saquinavir: When saquinavir is co-administered with ritonavir, consideration should be given to the potential effects of ritonavir on clarithromycin (refer to ritonavir above) [see Pharmacokinetics (12.3)] .
Etravirine		Etravirine: Clarithromycin exposure was decreased by etravirine; however, concentrations of the active metabolite, 14-OH-clarithromycin, were increased. Because 14-OH-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered; therefore alternatives to clarithromycin should be considered for the treatment of MAC.
Saquinavir (in patients with normal renal function)	No Dose Adjustment
Ritonavir (in patients with normal renal function)
Proton Pump Inhibitors:
Omeprazole	Use With Caution	Omeprazole: Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole [see Pharmacokinetics (12.3)] .
Miscellaneous Cytochrome P450 Inducers:
Efavirenz Nevirapine Rifampicin Rifabutin Rifapentine	Use With Caution	Inducers of CYP3A enzymes, such as efavirenz, nevirapine, rifampicin, rifabutin, and rifapentine will increase the metabolism of clarithromycin, thus decreasing plasma concentrations of clarithromycin, while increasing those of 14-OH-clarithromycin. Since the microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria, the intended therapeutic effect could be impaired during concomitant administration of clarithromycin and enzyme inducers. Alternative antibacterial treatment should be considered when treating patients receiving inducers of CYP3A. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with rifabutin (see Rifabutin under “Drugs That Are Affected By Clarithromycin” in the table above).

Table name:

Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

Table name:

Table 9: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s)	Recommendation	Comments
Tizanidine	Contraindicated	Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline	Avoid Use (Plasma Exposure Likely to be Increased and Prolonged)	Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate[see Warnings and Precautions (5.6).]
Drugs Known to Prolong QT Interval	Avoid Use	Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.10) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs	Use with caution Glucose-lowering effect potentiated	Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported. Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs. [see Adverse Reactions (6.1).]
Phenytoin	Use with caution Altered serum levels of phenytoin (increased and decreased)	To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after coadministration of ciprofloxacin with phenytoin.
Cyclosporine	Use with caution (transient elevations in serum creatinine)	Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs	Use with caution (Increase in anticoagulant effect)	The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate	Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels	Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole	Use with caution	Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin [see Warnings and Precautions (5.15)].
Clozapine	Use with caution	Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs	Use with caution	Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil	Use with caution 2-fold increase in exposure	Monitor for sildenafil toxicity (see Pharmacokinetics -(12.3)-].
Duloxetine	Avoid Use 5-fold increase in duloxetine exposure	If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives	Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life	Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx^® (didanosine) chewable/buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products)	Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2)].	Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid	Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels)	Potentiation of ciprofloxacin toxicity may occur.

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Do not co-administer the intravenous formulation in the same IV line with a multivalent cation, e.g., magnesium (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.11, 7.3)

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Specific Drugs Reported
also: diet high in vitamin K unreliable PT/INR determinations †Increased and decreased PT/INR responses have been reported.
alcohol† aminoglutethimide amobarbital atorvastatin† azathioprine butabarbital butalbital carbamazepine chloral hydrate† chlordiazepoxide chlorthalidone	cholestyramine† clozapine corticotropin cortisone cyclophosphamide† dicloxacillin ethchlorvynol glutethimide griseofulvin haloperidol meprobamate	6-mercaptopurine methimazole† moricizine hydrochloride† nafcillin paraldehyde pentobarbital phenobarbital phenytoin† pravastatin† prednisone† primidone	propylthiouracil† raloxifene ranitidine† rifampin secobarbital spironolactone sucralfate trazodone vitamin C (high dose) vitamin K warfarin underdosage

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Table 25: Clinically Important Drug Interactions with Aripiprazole:
Concomitant Drug Name or Drug Class	Clinical Rationale	Clinical Recommendation
Strong CYP3A4 Inhibitors (e.g., itraconazole, clarithromycin) or strong CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine)	The concomitant use of aripiprazole with strong CYP 3A4 or CYP2D6 inhibitors increased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3) ].	With concomitant use of aripiprazole with a strong CYP3A4 inhibitor or CYP2D6 inhibitor, reduce the aripiprazole dosage [see DOSAGE AND ADMINISTRATION(2.7) ] .
Strong CYP3A4 Inducers (e.g., carbamazepine, rifampin)	The concomitant use of aripiprazole and carbamazepine decreased the exposure of aripiprazole compared to the use of aripiprazole alone [see CLINICAL PHARMACOLOGY (12.3) ] .	With concomitant use of aripiprazole with a strong CYP3A4 inducer, consider increasing the aripiprazole dosage [see DOSAGE AND ADMINISTRATION(2.7) ] .
Antihypertensive Drugs	Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.	Monitor blood pressure and adjust dose accordingly [see WARNINGS AND PRECAUTIONS (5.8) ] .
Benzodiazepines (e.g., lorazepam)	The intensity of sedation was greater with the combination of oral aripiprazole and lorazepam as compared to that observed with aripiprazole alone. The orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepamalone [see WARNINGS AND PRECAUTIONS (5.8 )]	Monitor sedation and blood pressure. Adjust dose accordingly.

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Table III. Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.Refer to PRECAUTIONS, Drug Interactions for information regarding table.
albuterol,	famotidine	nizatidine
systemic and inhaled	felodipine	norfloxacin
amoxicillin	finasteride	ofloxacin
ampicillin,	hydrocortisone	omeprazole
with or without	isoflurane	prednisone, prednisolone
sulbactam	isoniazid	ranitidine
atenolol	isradipine	rifabutin
azithromycin	influenza vaccine	roxithromycin
caffeine,	ketoconazole	sorbitol
dietary digestion	lomefloxacin	(purgative doses do not
cefaclor	mebendazole	inhibit theophylline
co-trimoxazole	medroxyprogesterone	absorption)
(trimethoprim and	methylprednisolone	sucralfate
sulfamethoxazole)	metronidazole	terbutaline, systemic
diltiazem	metoprolol	terfenadine
dirithromycin	nadolol	tetracycline
enflurane	nifedipine	tocainide

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Table 18 Summary of Effect of Coadministered Drugs on Exposure to Active Moiety (Risperidone + 9-Hydroxy-Risperidone) in Healthy Subjects or Patients with Schizophrenia
Coadministered Drug	Dosing Schedule		Effect on Active Moiety (Risperidone + 9-Hydroxy-Risperidone (Ratio Change relative to reference)		Risperidone Dose Recommendation
Coadministered Drug	Coadministered Drug	Risperidone	AUC	Cmax	Risperidone Dose Recommendation
Enzyme (CYP2D6) Inhibitors
Fluoxetine	20 mg/day	2 or 3 mg twice daily	1.4	1.5	Re-evaluate dosing. Do not exceed 8 mg/day
Paroxetine	10 mg/day	4 mg/day	1.3	-	Re-evaluate dosing. Do not exceed 8 mg/day
	20 mg/day	4 mg/day	1.6	-
	40 mg/day	4 mg/day	1.8	-
Enzyme (CYP3A/PgP inducers) Inducers
Carbamazepine	573 ± 168 mg/day	3 mg twice daily	0.51	0.55	Titrate dose upwards. Do not exceed twice the patient's usual dose
Enzyme (CYP3A) Inhibitors
Ranitidine	150 mg twice daily	1 mg single dose	1.2	1.4	Dose adjustment not needed
Cimetidine	400 mg twice daily	1 mg single dose	1.1	1.3	Dose adjustment not needed
Erythromycin	500 mg four times daily	1 mg single dose	1.1	0.94	Dose adjustment not needed
Other Drugs
Amitriptyline	50 mg twice daily	3 mg twice daily	1.2	1.1	Dose adjustment not needed

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AED Co - administered	AED Concentration	Topiramate Concentration
Phenytoin	NCor25%increase^a	48%decrease
Carbamazepine(CBZ)	NC	40%decrease
CBZepoxide^b	NC	NE
Valproic acid	11%decrease	14%decrease
Phenobarbital	NC	NE
Primidone	NC	NE
Lamotrigine	NCatTPM dosesupto400 mg/day	13%decrease

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Interacting Drug	Interaction
Multivalent cation-containing products including antacids, metal cations or didanosine	Absorption of levofloxacin is decreased when the tablet formulation is taken within 2 hours of these products. (2.4, 7.1)
Warfarin	Effect may be enhanced. Monitor prothrombin time, INR, watch for bleeding (7.2)
Antidiabetic agents	Carefully monitor blood glucose (5.12, 7.3)

Table 7. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class: Drug Name	Effect on Concentration of Amprenavir or Concomitant Drug	Clinical Comment
HCV/HIV-Antiviral Agents
HCV protease inhibitor: Telaprevir^a	LEXIVA/ritonavir: ↓Amprenavir ↓Telaprevir	Coadministration of LEXIVA/ritonavir and telaprevir is not recommended.
HCV protease inhibitor: Boceprevir	LEXIVA/ritonavir: ↓Amprenavir (predicted) ↓Boceprevir (predicted)	Coadministration of LEXIVA/ritonavir and boceprevir is not recommended. A pharmacokinetic interaction has been reported between boceprevir and some HIV protease inhibitors in combination with ritonavir, leading to decreased HIV protease inhibitor concentrations and, in some cases, decreased boceprevir concentrations.
Non-nucleoside reverse transcriptase inhibitor: Efavirenz^a	LEXIVA: ↓Amprenavir LEXIVA/ritonavir: ↓Amprenavir	Appropriate doses of the combinations with respect to safety and efficacy have not been established. An additional 100 mg/day (300 mg total) of ritonavir is recommended when efavirenz is administered with LEXIVA/ritonavir once daily. No change in the ritonavir dose is required when efavirenz is administered with LEXIVA plus ritonavir twice daily.
Non-nucleoside reverse transcriptase inhibitor: Nevirapine^a	LEXIVA: ↓Amprenavir ↑Nevirapine LEXIVA/ritonavir: ↓Amprenavir ↑Nevirapine	Coadministration of nevirapine and LEXIVA without ritonavir is not recommended. No dosage adjustment required when nevirapine is administered with LEXIVA/ritonavir twice daily. The combination of nevirapine administered with LEXIVA/ritonavir once-daily regimen has not been studied.
HIV protease inhibitor: Atazanavir^a	LEXIVA: Interaction has not been evaluated. LEXIVA/ritonavir: ↓Atazanavir ↔Amprenavir	Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitors: Indinavir^a, nelfinavir^a	LEXIVA: ↑Amprenavir Effect on indinavir and nelfinavir is not well established. LEXIVA/ritonavir: Interaction has not been evaluated.	Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitors: Lopinavir/ritonavir^a	↓Amprenavir ↓Lopinavir	An increased rate of adverse events has been observed. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitor: Saquinavir^a	LEXIVA: ↓Amprenavir Effect on saquinavir is not well established. LEXIVA/ritonavir: Interaction has not been evaluated.	Appropriate doses of the combination with respect to safety and efficacy have not been established.
HIV integrase inhibitor: Raltegravir^a	LEXIVA: ↓Amprenavir ↓Raltegravir LEXIVA/ritonavir: ↓Amprenavir ↓Raltegravir	Appropriate doses of the combination with respect to safety and efficacy have not been established.
HIV CCR5 co-receptor antagonist: Maraviroc^a	LEXIVA/ritonavir: ↓Amprenavir ↑Maraviroc	No dosage adjustment required for LEXIVA/ritonavir. The recommended dose of maraviroc is 150 mg twice daily when coadministered with LEXIVA/ritonavir. LEXIVA should be given with ritonavir when coadministered with maraviroc.
Other Agents
Antiarrhythmics: Amiodarone, bepridil, lidocaine (systemic), and quinidine	↑Antiarrhythmics	Use with caution. Increased exposure may be associated with life-threatening reactions such as cardiac arrhythmias. Therapeutic concentration monitoring, if available, is recommended for antiarrhythmics.
Anticoagulant: Warfarin		Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: Carbamazepine, phenobarbital, phenytoin Phenytoin^a	LEXIVA: ↓Amprenavir LEXIVA/ritonavir: ↑Amprenavir ↓Phenytoin	Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations in patients taking these agents concomitantly. Plasma phenytoin concentrations should be monitored and phenytoin dose should be increased as appropriate. No change in LEXIVA/ritonavir dose is recommended.
Antidepressant: Paroxetine, trazodone	↓Paroxetine ↑Trazodone	Coadministration of paroxetine with LEXIVA/ritonavir significantly decreased plasma levels of paroxetine. Any paroxetine dose adjustment should be guided by clinical effect (tolerability and efficacy). Concomitant use of trazodone and LEXIVA with or without ritonavir may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as LEXIVA, the combination should be used with caution and a lower dose of trazodone should be considered.
Antifungals: Ketoconazole^a, itraconazole	↑Ketoconazole ↑Itraconazole	Increase monitoring for adverse events. LEXIVA: Dose reduction of ketoconazole or itraconazole may be needed for patients receiving more than 400 mg ketoconazole or itraconazole per day. LEXIVA/ritonavir: High doses of ketoconazole or itraconazole (greater than 200 mg/day) are not recommended.
Anti-gout: Colchicine	↑Colchicine	Patients with renal or hepatic impairment should not be given colchicine with LEXIVA/ritonavir. LEXIVA/ritonavir and coadministration of colchicine: Treatment of gout flares: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). LEXIVA and coadministration of colchicine: Treatment of gout flares: 1.2 mg (2 tablets) x 1 dose. Dose to be repeated no earlier than 3 days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg twice a day or 0.6 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once a day. Treatment of FMF: Maximum daily dose of 1.2 mg (may be given as 0.6 mg twice a day).
Antimycobacterial: Rifabutin^a	↑Rifabutin and rifabutin metabolite	A complete blood count should be performed weekly and as clinically indicated to monitor for neutropenia. LEXIVA: A dosage reduction of rifabutin by at least half the recommended dose is required. LEXIVA/ritonavir: Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (a maximum dose of 150 mg every other day or 3 times per week).
Benzodiazepines: Alprazolam, clorazepate, diazepam, flurazepam	↑Benzodiazepines	Clinical significance is unknown. A decrease in benzodiazepine dose may be needed.
Calcium channel blockers: Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine	↑Calcium channel blockers	Use with caution. Clinical monitoring of patients is recommended.
Corticosteroid: Dexamethasone	↓Amprenavir	Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations.
Endothelin-receptor antagonists: Bosentan	↑Bosentan	Coadministration of bosentan in patients on LEXIVA: In patients who have been receiving LEXIVA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability. Coadministration of LEXIVA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of LEXIVA. After at least 10 days following the initiation of LEXIVA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Histamine H₂-receptor antagonists: Cimetidine, famotidine, nizatidine, ranitidine^a	LEXIVA: ↓Amprenavir LEXIVA/ritonavir: Interaction not evaluated	Use with caution. LEXIVA may be less effective due to decreased amprenavir plasma concentrations.
HMG-CoA reductase inhibitors: Atorvastatin^a	↑Atorvastatin	Titrate atorvastatin dose carefully and use the lowest necessary dose; do not exceed atorvastatin 20 mg/day.
Immunosuppressants: Cyclosporine, tacrolimus, rapamycin	↑Immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents.
Inhaled beta-agonist: Salmeterol	↑Salmeterol	Concurrent administration of salmeterol with LEXIVA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Inhaled/nasal steroid: Fluticasone	LEXIVA: ↑Fluticasone LEXIVA/ritonavir: ↑Fluticasone	Use with caution. Consider alternatives to fluticasone, particularly for long-term use. May result in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone. Coadministration of fluticasone and LEXIVA/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
Narcotic analgesic: Methadone	↓Methadone	Data suggest that the interaction is not clinically relevant; however, patients should be monitored for opiate withdrawal symptoms.
Oral contraceptives: Ethinyl estradiol/norethindrone^a	LEXIVA: ↓Amprenavir ↓Ethinyl estradiol LEXIVA/ritonavir: ↓Ethinyl estradiol	Alternative methods of non-hormonal contraception are recommended. May lead to loss of virologic response. ^a Increased risk of transaminase elevations. No data are available on the use of LEXIVA/ritonavir with other hormonal therapies, such as hormone replacement therapy (HRT) for postmenopausal women.
PDE5 inhibitors: Sildenafil, tadalafil, vardenafil	↑Sildenafil ↑Tadalafil ↑Vardenafil	May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):
Proton pump inhibitors: Esomeprazole^a, lansoprazole, omeprazole, pantoprazole, rabeprazole	LEXIVA: ↔Amprenavir ↑Esomeprazole LEXIVA/ritonavir: ↔Amprenavir ↔Esomeprazole	Proton pump inhibitors can be administered at the same time as a dose of LEXIVA with no change in plasma amprenavir concentrations.
Tricyclic antidepressants: Amitriptyline, imipramine	↑Tricyclics	Therapeutic concentration monitoring is recommended for tricyclic antidepressants.

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Drugs That Increase Cyclosporine Concentrations
Calcium Channel Blockers	Antifungals	Antibiotics	Glucocorticoids	Other Drugs
diltiazem nicardipine verapamil	fluconazole itraconazole ketoconazole voriconazole	azithromycin clarithromycin erythromycin quinupristin/ dalfopristin	methylprednisolone	allopurinol amiodarone bromocriptine colchicine danazol imatinib metoclopramide nefazodoneoral contraceptives

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Table 2: Examples of CYP450 Interactions with Warfarin
Enzyme	Inhibitors	Inducers
CYP2C9	amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast	aprepitant, bosentan, carbamazepine, phenobarbital, rifampin
CYP1A2	acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton	montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking
CYP3A4	alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton	armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide

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Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3)
Interacting Agents	Prescribing Recommendations
Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir)	Avoid atorvastatin
HIV protease inhibitor (lopinavir plus ritonavir)	Use with caution and lowest dose necessary
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir)	Do not exceed 20 mg atorvastatin daily
HIV protease inhibitor (nelfinavir) Hepatitis C Protease inhibitor (boceprevir)	Do not exceed 40 mg atorvastatin daily

Table name:

Interacting Drug	Interaction
Theophylline	Serious and fatal reactions. Avoid concomitant use. Monitor serum level (7)
Warfarin	Anticoagulant effect enhanced. Monitor prothrombin time, INR, and bleeding (7)
Antidiabetic agents	Hypoglycemia including fatal outcomes have been reported. Monitor blood glucose (7)
Phenytoin	Monitor phenytoin level (7)
Methotrexate	Monitor for methotrexate toxicity (7)
Cyclosporine	May increase serum creatinine. Monitor serum creatinine (7)
Multivalent cation-containing products including antacids, metal cations or didanosine	Decreased ciprofloxacin absorption. Take 2 hours before or 6 hours after ciprofloxacin for oral suspension (7)